@article {133, title = {Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study.}, journal = {Gastroenterology}, volume = {160}, year = {2021}, month = {2021 Apr}, pages = {1620-1633.e13}, abstract = {

BACKGROUND \& AIMS: In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition.

METHODS: We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank.

RESULTS: Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5~{\texttimes} 10) and the replication studies (P < .05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score-defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1\% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7\%, 20.1\%, and 48.2\% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P < .001). Similarly, probability among those with extreme polygenic risk was 6.5\%, 10.3\%, and 19.5\% among individuals with normal weight, overweight, and obesity, respectively (P < .001).

CONCLUSIONS: Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.

}, issn = {1528-0012}, doi = {10.1053/j.gastro.2020.12.011}, author = {Emdin, Connor A and Haas, Mary and Ajmera, Veeral and Simon, Tracey G and Homburger, Julian and Neben, Cynthia and Jiang, Lan and Wei, Wei-Qi and Feng, Qiping and Zhou, Alicia and Denny, Joshua and Corey, Kathleen and Loomba, Rohit and Kathiresan, Sekar and Khera, Amit V} } @article {151, title = {Association of structural variation with cardiometabolic traits in Finns.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 04 01}, pages = {583-596}, abstract = {

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47~{\texttimes} 10) and is also associated with increased levels of total cholesterol (p = 1.22~{\texttimes} 10) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81~{\texttimes} 10) and alanine (p = 6.14~{\texttimes} 10) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24~{\texttimes} 10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53~{\texttimes} 10). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

}, keywords = {Alleles, Cardiovascular Diseases, Cholesterol, DNA Copy Number Variations, Female, Finland, Genome, Human, Genomic Structural Variation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Promoter Regions, Genetic, Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Pyruvic Acid, Serum Albumin, Human}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.03.008}, author = {Chen, Lei and Abel, Haley J and Das, Indraniel and Larson, David E and Ganel, Liron and Kanchi, Krishna L and Regier, Allison A and Young, Erica P and Kang, Chul Joo and Scott, Alexandra J and Chiang, Colby and Wang, Xinxin and Lu, Shuangjia and Christ, Ryan and Service, Susan K and Chiang, Charleston W K and Havulinna, Aki S and Kuusisto, Johanna and Boehnke, Michael and Laakso, Markku and Palotie, Aarno and Ripatti, Samuli and Freimer, Nelson B and Locke, Adam E and Stitziel, Nathan O and Hall, Ira M} } @article {152, title = {Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium.}, journal = {Genome Med}, volume = {13}, year = {2021}, month = {2021 04 21}, pages = {66}, abstract = {

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

}, keywords = {Adult, Aged, Aged, 80 and over, Angiotensin-Converting Enzyme 2, Asthma, Bronchi, Cardiovascular Diseases, COVID-19, Gene Expression, Genetic Variation, Humans, Middle Aged, Obesity, Pulmonary Disease, Chronic Obstructive, Quantitative Trait Loci, Respiratory Mucosa, Risk Factors, SARS-CoV-2, Smoking}, issn = {1756-994X}, doi = {10.1186/s13073-021-00866-2}, author = {Kasela, Silva and Ortega, Victor E and Martorella, Molly and Garudadri, Suresh and Nguyen, Jenna and Ampleford, Elizabeth and Pasanen, Anu and Nerella, Srilaxmi and Buschur, Kristina L and Barjaktarevic, Igor Z and Barr, R Graham and Bleecker, Eugene R and Bowler, Russell P and Comellas, Alejandro P and Cooper, Christopher B and Couper, David J and Criner, Gerard J and Curtis, Jeffrey L and Han, MeiLan K and Hansel, Nadia N and Hoffman, Eric A and Kaner, Robert J and Krishnan, Jerry A and Martinez, Fernando J and McDonald, Merry-Lynn N and Meyers, Deborah A and Paine, Robert and Peters, Stephen P and Castro, Mario and Denlinger, Loren C and Erzurum, Serpil C and Fahy, John V and Israel, Elliot and Jarjour, Nizar N and Levy, Bruce D and Li, Xingnan and Moore, Wendy C and Wenzel, Sally E and Zein, Joe and Langelier, Charles and Woodruff, Prescott G and Lappalainen, Tuuli and Christenson, Stephanie A} } @article {154, title = {Genetic Predictor to Identify Individuals With High Lipoprotein(a) Concentrations.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Feb}, pages = {e003182}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003182}, author = {Dron, Jacqueline S and Wang, Minxian and Patel, Aniruddh P and Kartoun, Uri and Ng, Kenney and Hegele, Robert A and Khera, Amit V} } @article {159, title = {Genetic profiles of 103,106 individuals in the Taiwan Biobank provide insights into the health and history of Han Chinese.}, journal = {NPJ Genom Med}, volume = {6}, year = {2021}, month = {2021 Feb 11}, pages = {10}, abstract = {

Personalized medical care focuses on prediction of disease risk and response to medications. To build the risk models, access to both large-scale genomic resources and human genetic studies is required. The Taiwan Biobank (TWB) has generated high-coverage, whole-genome sequencing data from 1492 individuals and genome-wide SNP data from 103,106 individuals of Han Chinese ancestry using custom SNP arrays. Principal components analysis of the genotyping data showed that the full range of Han Chinese genetic variation was found in the cohort. The arrays also include thousands of known functional variants, allowing for simultaneous ascertainment of Mendelian disease-causing mutations and variants that affect drug metabolism. We found that 21.2\% of the population are mutation carriers of autosomal recessive diseases, 3.1\% have mutations in cancer-predisposing genes, and 87.3\% carry variants that affect drug response. We highlight how TWB data provide insight into both population history and disease burden, while showing how widespread genetic testing can be used to improve clinical care.

}, issn = {2056-7944}, doi = {10.1038/s41525-021-00178-9}, author = {Wei, Chun-Yu and Yang, Jenn-Hwai and Yeh, Erh-Chan and Tsai, Ming-Fang and Kao, Hsiao-Jung and Lo, Chen-Zen and Chang, Lung-Pao and Lin, Wan-Jia and Hsieh, Feng-Jen and Belsare, Saurabh and Bhaskar, Anand and Su, Ming-Wei and Lee, Te-Chang and Lin, Yi-Ling and Liu, Fu-Tong and Shen, Chen-Yang and Li, Ling-Hui and Chen, Chien-Hsiun and Wall, Jeffrey D and Wu, Jer-Yuarn and Kwok, Pui-Yan} } @article {149, title = {Germline mutation in : a heterogeneous, multi-systemic developmental disorder characterized by transcriptional dysregulation.}, journal = {HGG Adv}, volume = {2}, year = {2021}, month = {2021 Jan 14}, abstract = {

germline variation in was recently reported to associate with a neurodevelopmental disorder. We report twelve individuals harboring putatively pathogenic or inherited variants in , detail their phenotypes, and map all known variants to the domain structure of and crystal structure of RNA polymerase II. Affected individuals were ascertained from a local data lake, pediatric genetics clinic, and an online community of families of affected individuals. These include six affected by missense variants (including one previously reported individual), four clinical laboratory samples affected by missense variation with unknown inheritance-with yeast functional assays further supporting altered function-one affected by a in-frame deletion, and one affected by a C-terminal frameshift variant inherited from a largely asymptomatic mother. Recurrently observed phenotypes include ataxia, joint hypermobility, short stature, skin abnormalities, congenital cardiac abnormalities, immune system abnormalities, hip dysplasia, and short Achilles tendons. We report a significantly higher occurrence of epilepsy (8/12, 66.7\%) than previously reported (3/15, 20\%) (p value = 0.014196; chi-square test) and a lower occurrence of hypotonia (8/12, 66.7\%) than previously reported (14/15, 93.3\%) (p value = 0.076309). -related developmental disorders likely represent a spectrum of related, multi-systemic developmental disorders, driven by distinct mechanisms, converging at a single locus.

}, issn = {2666-2477}, doi = {10.1016/j.xhgg.2020.100014}, author = {Hansen, Adam W and Arora, Payal and Khayat, Michael M and Smith, Leah J and Lewis, Andrea M and Rossetti, Linda Z and Jayaseelan, Joy and Cristian, Ingrid and Haynes, Devon and DiTroia, Stephanie and Meeks, Naomi and Delgado, Mauricio R and Rosenfeld, Jill A and Pais, Lynn and White, Susan M and Meng, Qingchang and Pehlivan, Davut and Liu, Pengfei and Gingras, Marie-Claude and Wangler, Michael F and Muzny, Donna M and Lupski, James R and Kaplan, Craig D and Gibbs, Richard A} } @article {156, title = {Haplotype-resolved diverse human genomes and integrated analysis of structural variation.}, journal = {Science}, volume = {372}, year = {2021}, month = {2021 04 02}, abstract = {

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50\% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68\% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63\% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

}, keywords = {Female, Genetic Variation, Genome, Human, Genotype, Haplotypes, High-Throughput Nucleotide Sequencing, Humans, INDEL Mutation, Interspersed Repetitive Sequences, Male, Population Groups, Quantitative Trait Loci, Retroelements, Sequence Analysis, DNA, Sequence Inversion, Whole Genome Sequencing}, issn = {1095-9203}, doi = {10.1126/science.abf7117}, author = {Ebert, Peter and Audano, Peter A and Zhu, Qihui and Rodriguez-Martin, Bernardo and Porubsky, David and Bonder, Marc Jan and Sulovari, Arvis and Ebler, Jana and Zhou, Weichen and Serra Mari, Rebecca and Yilmaz, Feyza and Zhao, Xuefang and Hsieh, PingHsun and Lee, Joyce and Kumar, Sushant and Lin, Jiadong and Rausch, Tobias and Chen, Yu and Ren, Jingwen and Santamarina, Martin and H{\"o}ps, Wolfram and Ashraf, Hufsah and Chuang, Nelson T and Yang, Xiaofei and Munson, Katherine M and Lewis, Alexandra P and Fairley, Susan and Tallon, Luke J and Clarke, Wayne E and Basile, Anna O and Byrska-Bishop, Marta and Corvelo, Andr{\'e} and Evani, Uday S and Lu, Tsung-Yu and Chaisson, Mark J P and Chen, Junjie and Li, Chong and Brand, Harrison and Wenger, Aaron M and Ghareghani, Maryam and Harvey, William T and Raeder, Benjamin and Hasenfeld, Patrick and Regier, Allison A and Abel, Haley J and Hall, Ira M and Flicek, Paul and Stegle, Oliver and Gerstein, Mark B and Tubio, Jose M C and Mu, Zepeng and Li, Yang I and Shi, Xinghua and Hastie, Alex R and Ye, Kai and Chong, Zechen and Sanders, Ashley D and Zody, Michael C and Talkowski, Michael E and Mills, Ryan E and Devine, Scott E and Lee, Charles and Korbel, Jan O and Marschall, Tobias and Eichler, Evan E} } @article {119, title = {Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells.}, journal = {Cell}, volume = {184}, year = {2021}, month = {2021 01 07}, pages = {92-105.e16}, abstract = {

To better understand host-virus genetic dependencies and find potential therapeutic targets for COVID-19, we performed a genome-scale CRISPR loss-of-function screen to identify host factors required for SARS-CoV-2 viral infection of human alveolar epithelial cells. Top-ranked genes cluster into distinct pathways, including the vacuolar ATPase proton pump, Retromer, and Commander complexes. We validate these gene targets using several orthogonal methods such as CRISPR knockout, RNA interference knockdown, and small-molecule inhibitors. Using single-cell RNA-sequencing, we identify shared transcriptional changes in cholesterol biosynthesis upon loss of top-ranked genes. In addition, given the key role of the ACE2 receptor in the early stages of viral entry, we show that loss of RAB7A reduces viral entry by sequestering the ACE2 receptor inside cells. Overall, this work provides a genome-scale, quantitative resource of the impact of the loss of each host gene on fitness/response to viral infection.

}, keywords = {A549 Cells, Alveolar Epithelial Cells, Angiotensin-Converting Enzyme 2, Biosynthetic Pathways, Cholesterol, Clustered Regularly Interspaced Short Palindromic Repeats, COVID-19, Endosomes, Gene Expression Profiling, Gene Knockdown Techniques, Gene Knockout Techniques, Genome-Wide Association Study, Host-Pathogen Interactions, Humans, rab GTP-Binding Proteins, rab7 GTP-Binding Proteins, RNA Interference, SARS-CoV-2, Single-Cell Analysis, Viral Load}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.10.030}, author = {Daniloski, Zharko and Jordan, Tristan X and Wessels, Hans-Hermann and Hoagland, Daisy A and Kasela, Silva and Legut, Mateusz and Maniatis, Silas and Mimitou, Eleni P and Lu, Lu and Geller, Evan and Danziger, Oded and Rosenberg, Brad R and Phatnani, Hemali and Smibert, Peter and Lappalainen, Tuuli and tenOever, Benjamin R and Sanjana, Neville E} } @article {158, title = {Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein-truncating alleles in Xia-Gibbs syndrome.}, journal = {Hum Mutat}, volume = {42}, year = {2021}, month = {2021 May}, pages = {577-591}, abstract = {

Xia-Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop-gain or frameshift mutations in the AT-hook DNA binding motif containing 1 (AHDC1) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80\% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid-protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.

}, issn = {1098-1004}, doi = {10.1002/humu.24190}, author = {Khayat, Michael M and Li, He and Chander, Varuna and Hu, Jianhong and Hansen, Adam W and Li, Shoudong and Traynelis, Josh and Shen, Hua and Weissenberger, George and Stossi, Fabio and Johnson, Hannah L and Lupski, James R and Posey, Jennifer E and Sabo, Aniko and Meng, Qingchang and Murdock, David R and Wangler, Michael and Gibbs, Richard A} } @article {157, title = {Phylogenetic history of patrilineages rare in northern and eastern Europe from large-scale re-sequencing of human Y-chromosomes.}, journal = {Eur J Hum Genet}, year = {2021}, month = {2021 May 07}, abstract = {

The most frequent Y-chromosomal (chrY) haplogroups in northern and eastern Europe (NEE) are well-known and thoroughly characterised. Yet a considerable number of men in every population carry rare paternal lineages with estimated frequencies around 5\%. So far, limited sample-sizes and insufficient resolution of genotyping have obstructed a truly comprehensive look into the variety of rare paternal lineages segregating within populations and potential signals of population history that such lineages might convey. Here we harness the power of massive re-sequencing of human Y chromosomes to identify previously unknown population-specific clusters among rare paternal lineages in NEE. We construct dated phylogenies for haplogroups E2-M215, J2-M172, G-M201 and Q-M242 on the basis of 421 (of them 282 novel) high-coverage chrY sequences collected from large-scale databases focusing on populations of NEE. Within these otherwise rare haplogroups we disclose lineages that began to radiate ~1-3 thousand years ago in Estonia and Sweden and reveal male phylogenetic patterns testifying of comparatively recent local demographic expansions. Conversely, haplogroup Q lineages bear evidence of ancient Siberian influence lingering in the modern paternal gene pool of northern Europe. We assess the possible direction of influx of ancestral carriers for some of these male lineages. In addition, we demonstrate the congruency of paternal haplogroup composition of our dataset with two independent population-based cohorts from Estonia and Sweden.

}, issn = {1476-5438}, doi = {10.1038/s41431-021-00897-8}, author = {Ilum{\"a}e, Anne-Mai and Post, Helen and Flores, Rodrigo and Karmin, Monika and Sahakyan, Hovhannes and Mondal, Mayukh and Montinaro, Francesco and Saag, Lauri and Bormans, Concetta and Sanchez, Luisa Fernanda and Ameur, Adam and Gyllensten, Ulf and Kals, Mart and M{\"a}gi, Reedik and Pagani, Luca and Behar, Doron M and Rootsi, Siiri and Villems, Richard} } @article {160, title = {SVEP1 is a human coronary artery disease locus that promotes atherosclerosis.}, journal = {Sci Transl Med}, volume = {13}, year = {2021}, month = {2021 Mar 24}, abstract = {

A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1 and is further increased by the coronary disease-associated variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Together, our results suggest that VSMC-derived SVEP1 is a proatherogenic factor and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

}, issn = {1946-6242}, doi = {10.1126/scitranslmed.abe0357}, author = {Jung, In-Hyuk and Elenbaas, Jared S and Alisio, Arturo and Santana, Katherine and Young, Erica P and Kang, Chul Joo and Kachroo, Puja and Lavine, Kory J and Razani, Babak and Mecham, Robert P and Stitziel, Nathan O} } @article {142, title = {Transethnic Transferability of a Genome-Wide Polygenic Score for Coronary Artery Disease.}, journal = {Circ Genom Precis Med}, volume = {14}, year = {2021}, month = {2021 Feb}, pages = {e003092}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.120.003092}, author = {Fahed, Akl C and Aragam, Krishna G and Hindy, George and Chen, Yii-Der Ida and Chaudhary, Kumardeep and Dobbyn, Amanda and Krumholz, Harlan M and Sheu, Wayne H H and Rich, Stephen S and Rotter, Jerome I and Chowdhury, Rajiv and Cho, Judy and Do, Ron and Ellinor, Patrick T and Kathiresan, Sekar and Khera, Amit V} } @article {155, title = {Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 03 04}, pages = {431-445}, abstract = {

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.

}, keywords = {African Americans, Aged, Aged, 80 and over, Calbindin 2, Colitis, Ulcerative, Crohn Disease, European Continental Ancestry Group, Female, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Inflammatory Bowel Diseases, Male, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Receptors, Prostaglandin E, EP4 Subtype, Whole Genome Sequencing}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.02.001}, author = {Somineni, Hari K and Nagpal, Sini and Venkateswaran, Suresh and Cutler, David J and Okou, David T and Haritunians, Talin and Simpson, Claire L and Begum, Ferdouse and Datta, Lisa W and Quiros, Antonio J and Seminerio, Jenifer and Mengesha, Emebet and Alexander, Jonathan S and Baldassano, Robert N and Dudley-Brown, Sharon and Cross, Raymond K and Dassopoulos, Themistocles and Denson, Lee A and Dhere, Tanvi A and Iskandar, Heba and Dryden, Gerald W and Hou, Jason K and Hussain, Sunny Z and Hyams, Jeffrey S and Isaacs, Kim L and Kader, Howard and Kappelman, Michael D and Katz, Jeffry and Kellermayer, Richard and Kuemmerle, John F and Lazarev, Mark and Li, Ellen and Mannon, Peter and Moulton, Dedrick E and Newberry, Rodney D and Patel, Ashish S and Pekow, Joel and Saeed, Shehzad A and Valentine, John F and Wang, Ming-Hsi and McCauley, Jacob L and Abreu, Maria T and Jester, Traci and Molle-Rios, Zarela and Palle, Sirish and Scherl, Ellen J and Kwon, John and Rioux, John D and Duerr, Richard H and Silverberg, Mark S and Zwick, Michael E and Stevens, Christine and Daly, Mark J and Cho, Judy H and Gibson, Greg and McGovern, Dermot P B and Brant, Steven R and Kugathasan, Subra} } @article {117, title = {Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 05 07}, pages = {2254}, abstract = {

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM.

}, keywords = {Cardiomyopathy, Dilated, Genome-Wide Association Study, Heart, Humans, Magnetic Resonance Imaging, Myocardium, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/s41467-020-15823-7}, author = {Pirruccello, James P and Bick, Alexander and Wang, Minxian and Chaffin, Mark and Friedman, Samuel and Yao, Jie and Guo, Xiuqing and Venkatesh, Bharath Ambale and Taylor, Kent D and Post, Wendy S and Rich, Stephen and Lima, Joao A C and Rotter, Jerome I and Philippakis, Anthony and Lubitz, Steven A and Ellinor, Patrick T and Khera, Amit V and Kathiresan, Sekar and Aragam, Krishna G} } @article {144, title = {Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 04 01}, pages = {e203959}, abstract = {

Importance: Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening.

Objectives: To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care.

Design, Setting, and Participants: This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019.

Exposures: Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist.

Main Outcomes and Measures: Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome.

Results: Among 49 738 participants (mean [SD] age, 57 [8] years; 27 144 female [55\%]), 441 (0.9\%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3\%) for familial hypercholesterolemia, 235 (0.5\%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2\%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4\%) vs 4663 of 49 607 noncarriers (9.4\%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6\%) vs 2080 of 27 028 female noncarriers (7.7\%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4\%) vs 929 of 49 662 noncarriers (1.9\%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3\% for carriers of familial hypercholesterolemia, 41.1\% for hereditary breast and ovarian cancer syndrome, and 38.3\% for Lynch syndrome. Across the 3 conditions, 39.7\% (175 of 441) of the carriers reported a family history of disease vs 23.2\% (34 517 of 148 772) of noncarriers.

Conclusions and Relevance: The findings suggest that approximately 1\% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.

}, keywords = {Aged, Cohort Studies, Colorectal Neoplasms, Hereditary Nonpolyposis, Female, Genetic Predisposition to Disease, Hereditary Breast and Ovarian Cancer Syndrome, Heterozygote, Humans, Hyperlipoproteinemia Type II, Male, Middle Aged, Pedigree, Proportional Hazards Models, United Kingdom, Whole Exome Sequencing}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.3959}, author = {Patel, Aniruddh P and Wang, Minxian and Fahed, Akl C and Mason-Suares, Heather and Brockman, Deanna and Pelletier, Renee and Amr, Sami and Machini, Kalotina and Hawley, Megan and Witkowski, Leora and Koch, Christopher and Philippakis, Anthony and Cassa, Christopher A and Ellinor, Patrick T and Kathiresan, Sekar and Ng, Kenney and Lebo, Matthew and Khera, Amit V} } @article {99, title = {Cell type-specific genetic regulation of gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

}, keywords = {Cells, Gene Expression Regulation, Humans, Organ Specificity, Quantitative Trait Loci, RNA, Long Noncoding, Transcriptome}, issn = {1095-9203}, doi = {10.1126/science.aaz8528}, author = {Kim-Hellmuth, Sarah and Aguet, Fran{\c c}ois and Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kasela, Silva and Wucher, Valentin and Castel, Stephane E and Hamel, Andrew R and Vi{\~n}uela, Ana and Roberts, Amy L and Mangul, Serghei and Wen, Xiaoquan and Wang, Gao and Barbeira, Alvaro N and Garrido-Mart{\'\i}n, Diego and Nadel, Brian B and Zou, Yuxin and Bonazzola, Rodrigo and Quan, Jie and Brown, Andrew and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Getz, Gad and Dermitzakis, Emmanouil T and Small, Kerrin S and Stephens, Matthew and Xi, Hualin S and Im, Hae Kyung and Guigo, Roderic and Segr{\`e}, Ayellet V and Stranger, Barbara E and Ardlie, Kristin G and Lappalainen, Tuuli} } @article {95, title = {Combining Imaging and Genetics to Predict Recurrence of Anticoagulation-Associated Intracerebral Hemorrhage.}, journal = {Stroke}, volume = {51}, year = {2020}, month = {2020 07}, pages = {2153-2160}, abstract = {

BACKGROUND AND PURPOSE: For survivors of oral anticoagulation therapy (OAT)-associated intracerebral hemorrhage (OAT-ICH) who are at high risk for thromboembolism, the benefits of OAT resumption must be weighed against increased risk of recurrent hemorrhagic stroke. The ε2/ε4 alleles of the () gene, MRI-defined cortical superficial siderosis, and cerebral microbleeds are the most potent risk factors for recurrent ICH. We sought to determine whether combining MRI markers and genotype could have clinical impact by identifying ICH survivors in whom the risks of OAT resumption are highest.

METHODS: Joint analysis of data from 2 longitudinal cohort studies of OAT-ICH survivors: (1) MGH-ICH study (Massachusetts General Hospital ICH) and (2) longitudinal component of the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage). We evaluated whether MRI markers and genotype predict ICH recurrence. We then developed and validated a combined -MRI classification scheme to predict ICH recurrence, using Classification and Regression Tree analysis.

RESULTS: Cortical superficial siderosis, cerebral microbleed, and ε2/ε4 variants were independently associated with ICH recurrence after OAT-ICH (all <0.05). Combining genotype and MRI data resulted in improved prediction of ICH recurrence (Harrell C: 0.79 versus 0.55 for clinical data alone, =0.033). In the MGH (training) data set, CSS, cerebral microbleed, and ε2/ε4 stratified likelihood of ICH recurrence into high-, medium-, and low-risk categories. In the ERICH (validation) data set, yearly ICH recurrence rates for high-, medium-, and low-risk individuals were 6.6\%, 2.5\%, and 0.9\%, respectively, with overall area under the curve of 0.91 for prediction of recurrent ICH.

CONCLUSIONS: Combining MRI and genotype stratifies likelihood of ICH recurrence into high, medium, and low risk. If confirmed in prospective studies, this combined -MRI classification scheme may prove useful for selecting individuals for OAT resumption after ICH.

}, keywords = {Aged, Anticoagulants, Apolipoprotein E4, Cerebral Hemorrhage, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Neuroimaging, Recurrence}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.120.028310}, author = {Biffi, Alessandro and Urday, Sebastian and Kubiszewski, Patryk and Gilkerson, Lee and Sekar, Padmini and Rodriguez-Torres, Axana and Bettin, Margaret and Charidimou, Andreas and Pasi, Marco and Kourkoulis, Christina and Schwab, Kristin and DiPucchio, Zora and Behymer, Tyler and Osborne, Jennifer and Morgan, Misty and Moomaw, Charles J and James, Michael L and Greenberg, Steven M and Viswanathan, Anand and Gurol, M Edip and Worrall, Bradford B and Testai, Fernando D and McCauley, Jacob L and Falcone, Guido J and Langefeld, Carl D and Anderson, Christopher D and Kamel, Hooman and Woo, Daniel and Sheth, Kevin N and Rosand, Jonathan} } @article {146, title = {A common variant in PNPLA3 is associated with age at diagnosis of NAFLD in patients from a multi-ethnic biobank.}, journal = {J Hepatol}, volume = {72}, year = {2020}, month = {2020 06}, pages = {1070-1081}, abstract = {

BACKGROUND \& AIMS: The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis.

METHODS: We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n~= 1,703) and confirming controls (n~= 8,119). We conducted i) a survival analysis to determine if age at diagnosis differed by rs738409 genotype, ii) a receiver operating characteristics analysis to assess the utility of the rs738409 genotype in discriminating NAFLD cases from controls, and iii) a phenome-wide association study (PheWAS) between rs738409 and 10,095 EHR-derived disease diagnoses.

RESULTS: The PNPLA3 G risk allele was associated with: i) earlier age of NAFLD diagnosis, with the strongest effect in Hispanics (hazard ratio 1.33; 95\% CI 1.15-1.53; p <0.0001) among whom a NAFLD diagnosis was 15\% more likely in risk allele carriers vs. non-carriers; ii) increased NAFLD risk (odds ratio 1.61; 95\% CI 1.349-1.73; p <0.0001), with the strongest effect among Hispanics (odds ratio 1.43; 95\% CI 1.28-1.59; p <0.0001); iii) additional liver diseases in a PheWAS (p <4.95~{\texttimes} 10) where the risk variant also associated with earlier age of diagnosis.

CONCLUSION: Given the role of the rs738409 in NAFLD diagnosis age, our results suggest that stratifying risk within populations known to have an enhanced risk of liver disease, such as Hispanic carriers of the rs738409 variant, would be effective in earlier identification of those who would benefit most from early NAFLD prevention and treatment strategies.

LAY SUMMARY: Despite clear associations between the PNPLA3 rs738409 variant and elevated risk of progression from non-alcoholic fatty liver disease (NAFLD) to more severe forms of liver disease, it remains unknown if PNPLA3 rs738409 plays a role in the age of NAFLD onset. Herein, we found that this risk variant is associated with an earlier age of NAFLD and other liver disease diagnoses; an observation most pronounced in Hispanic Americans. We conclude that PNPLA3 rs738409 could be used to better understand liver disease risk within vulnerable populations and identify patients that may benefit from early prevention strategies.

}, issn = {1600-0641}, doi = {10.1016/j.jhep.2020.01.029}, author = {Walker, Ryan W and Belbin, Gillian M and Sorokin, Elena P and Van Vleck, Tielman and Wojcik, Genevieve L and Moscati, Arden and Gignoux, Christopher R and Cho, Judy and Abul-Husn, Noura S and Nadkarni, Girish and Kenny, Eimear E and Loos, Ruth J F} } @article {138, title = {Complex mosaic structural variations in human fetal brains.}, journal = {Genome Res}, volume = {30}, year = {2020}, month = {2020 12}, pages = {1695-1704}, abstract = {

Somatic mosaicism, manifesting as single nucleotide variants (SNVs), mobile element insertions, and structural changes in the DNA, is a common phenomenon in human brain cells, with potential functional consequences. Using a clonal approach, we previously detected 200-400 mosaic SNVs per cell in three human fetal brains (15-21 wk postconception). However, structural variation in the human fetal brain has not yet been investigated. Here, we discover and validate four mosaic structural variants (SVs) in the same brains and resolve their precise breakpoints. The SVs were of kilobase scale and complex, consisting of deletion(s) and rearranged genomic fragments, which sometimes originated from different chromosomes. Sequences at the breakpoints of these rearrangements had microhomologies, suggesting their origin from replication errors. One SV was found in two clones, and we timed its origin to \~{}14 wk postconception. No large scale mosaic copy number variants (CNVs) were detectable in normal fetal human brains, suggesting that previously reported megabase-scale CNVs in neurons arise at later stages of development. By reanalysis of public single nuclei data from adult brain neurons, we detected an extrachromosomal circular DNA event. Our study reveals the existence of mosaic SVs in the developing human brain, likely arising from cell proliferation during mid-neurogenesis. Although relatively rare compared to SNVs and present in \~{}10\% of neurons, SVs in developing human brain affect a comparable number of bases in the genome (\~{}6200 vs. \~{}4000 bp), implying that they may have similar functional consequences.

}, issn = {1549-5469}, doi = {10.1101/gr.262667.120}, author = {Sekar, Shobana and Tomasini, Livia and Proukakis, Christos and Bae, Taejeong and Manlove, Logan and Jang, Yeongjun and Scuderi, Soraya and Zhou, Bo and Kalyva, Maria and Amiri, Anahita and Mariani, Jessica and Sedlazeck, Fritz J and Urban, Alexander E and Vaccarino, Flora M and Abyzov, Alexej} } @article {100, title = {Determinants of telomere length across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

}, keywords = {Aging, Genetic Markers, Genetic Variation, Humans, Organ Specificity, Telomere, Telomere Homeostasis, Telomere Shortening}, issn = {1095-9203}, doi = {10.1126/science.aaz6876}, author = {Demanelis, Kathryn and Jasmine, Farzana and Chen, Lin S and Chernoff, Meytal and Tong, Lin and Delgado, Dayana and Zhang, Chenan and Shinkle, Justin and Sabarinathan, Mekala and Lin, Hannah and Ramirez, Eduardo and Oliva, Meritxell and Kim-Hellmuth, Sarah and Stranger, Barbara E and Lai, Tsung-Po and Aviv, Abraham and Ardlie, Kristin G and Aguet, Fran{\c c}ois and Ahsan, Habibul and Doherty, Jennifer A and Kibriya, Muhammad G and Pierce, Brandon L} } @article {145, title = {Development and validation of the VISAGE AmpliSeq basic tool to predict appearance and ancestry from DNA.}, journal = {Forensic Sci Int Genet}, volume = {48}, year = {2020}, month = {2020 09}, pages = {102336}, abstract = {

Forensic DNA phenotyping is gaining interest as the number of applications increases within the forensic genetics community. The possibility of providing investigative leads in addition to conventional DNA profiling for human identification provides new insights into otherwise "cold" police investigations. The ability of reporting on the bio-geographical ancestry (BGA), appearance characteristics and age based on DNA obtained from a crime scene sample of an unknown donor makes the exploration of such markers and the development of new methods meaningful for criminal investigations. The VISible Attributes through GEnomics (VISAGE) Consortium aims to disseminate and broaden the use of predictive markers and develop fully optimized and validated prototypes for forensic casework implementation. Here, the first VISAGE appearance and ancestry tool development, performance and validation is reported. A total of 153 SNPs (96.84 \% assay conversion rate) were successfully incorporated into a single multiplex reaction using the AmpliSeq{\texttrademark} design pipeline, and applied for massively parallel sequencing with the Ion S5 platform. A collaborative effort involving six VISAGE laboratory partners was devised to perform all validation tests. An extensive validation plan was carefully organized to explore the assay{\textquoteright}s overall performance with optimum and low-input samples, as well as with challenging and casework mock samples. In addition, forensic validation studies such as concordance and mixture tests recurring to the Coriell sample set with known genotypes were performed. Finally, inhibitor tolerance and specificity were also evaluated. Results showed a robust, highly sensitive assay with good overall concordance between laboratories.

}, issn = {1878-0326}, doi = {10.1016/j.fsigen.2020.102336}, author = {Xavier, Catarina and de la Puente, Mar{\'\i}a and Mosquera-Miguel, Ana and Freire-Aradas, Ana and Kalamara, Vivian and Vidaki, Athina and E Gross, Theresa and Revoir, Andrew and Po{\'s}piech, Ewelina and Kartasi{\'n}ska, Ewa and Sp{\'o}lnicka, Magdalena and Branicki, Wojciech and E Ames, Carole and M Schneider, Peter and Hohoff, Carsten and Kayser, Manfred and Phillips, Christopher and Parson, Walther} } @article {110, title = {Discovery and population genomics of structural variation in a songbird genus.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 07 07}, pages = {3403}, abstract = {

Structural variation~(SV) constitutes an important type of genetic mutations providing the raw material for evolution. Here, we uncover the genome-wide spectrum of intra- and interspecific SV segregating in natural populations of seven songbird species in the genus Corvus. Combining short-read (N = 127) and long-read re-sequencing (N = 31), as well as optical mapping (N = 16), we apply both assembly- and read mapping approaches to detect SV and characterize a total of 220,452 insertions, deletions and inversions. We exploit sampling across wide phylogenetic timescales to validate SV genotypes and assess the contribution of SV to evolutionary processes in an avian model of incipient speciation. We reveal an evolutionary young (~530,000 years) cis-acting 2.25-kb LTR retrotransposon insertion reducing expression of the NDP gene with consequences for premating isolation. Our results attest to the wealth and evolutionary significance of SV segregating in natural populations and highlight the need for reliable SV genotyping.

}, keywords = {Animals, Chromosome Inversion, Gene Deletion, Genetic Variation, Genetics, Population, Genome, Genomic Structural Variation, Genotype, Phylogeny, Polymorphism, Single Nucleotide, Retroelements, Sequence Analysis, DNA, Songbirds}, issn = {2041-1723}, doi = {10.1038/s41467-020-17195-4}, author = {Weissensteiner, Matthias H and Bunikis, Ignas and Catal{\'a}n, Ana and Francoijs, Kees-Jan and Knief, Ulrich and Heim, Wieland and Peona, Valentina and Pophaly, Saurabh D and Sedlazeck, Fritz J and Suh, Alexander and Warmuth, Vera M and Wolf, Jochen B W} } @article {115, title = {Emerging Targets for Cardiovascular Disease Prevention in Diabetes.}, journal = {Trends Mol Med}, volume = {26}, year = {2020}, month = {2020 08}, pages = {744-757}, abstract = {

Type 1 and type 2 diabetes mellitus (T1DM and T2DM) increase the risk of atherosclerotic cardiovascular disease (CVD), resulting in acute cardiovascular events, such as heart attack and stroke. Recent clinical trials point toward new treatment and prevention strategies for cardiovascular complications of T2DM. New antidiabetic agents show unexpected cardioprotective benefits. Moreover, genetic and reverse translational strategies have revealed potential novel targets for CVD prevention in diabetes, including inhibition of apolipoprotein C3 (APOC3). Modeling and pharmacology-based approaches to improve insulin action provide additional potential strategies to combat CVD. The development of new strategies for improved diabetes and lipid control fuels hope for future prevention of CVD associated with diabetes.

}, issn = {1471-499X}, doi = {10.1016/j.molmed.2020.03.011}, author = {Stitziel, Nathan O and Kanter, Jenny E and Bornfeldt, Karin E} } @article {111, title = {Evaluation of the VISAGE Basic Tool for Appearance and Ancestry Prediction Using PowerSeq Chemistry on the MiSeq FGx System.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 06 26}, abstract = {

The study of DNA to predict externally visible characteristics (EVCs) and the biogeographical ancestry (BGA) from unknown samples is gaining relevance in forensic genetics. Technical developments in Massively Parallel Sequencing (MPS) enable the simultaneous analysis of hundreds of DNA markers, which improves successful Forensic DNA Phenotyping (FDP). The EU-funded VISAGE (VISible Attributes through GEnomics) Consortium has developed various targeted MPS-based lab tools to apply FDP in routine forensic analyses. Here, we present an evaluation of the VISAGE Basic tool for appearance and ancestry prediction based on PowerSeq chemistry (Promega) on a MiSeq FGx System (Illumina). The panel consists of 153 single nucleotide polymorphisms (SNPs) that provide information about EVCs (41 SNPs for eye, hair and skin color from HIrisPlex-S) and continental BGA (115 SNPs; three overlap with the EVCs SNP set). The assay was evaluated for sensitivity, repeatability and genotyping concordance, as well as its performance with casework-type samples. This targeted MPS assay provided complete genotypes at all 153 SNPs down to 125 pg of input DNA and 99.67\% correct genotypes at 50 pg. It was robust in terms of repeatability and concordance and provided useful results with casework-type samples. The results suggest that this MPS assay is a useful tool for basic appearance and ancestry prediction in forensic genetics for users interested in applying PowerSeq chemistry and MiSeq for this purpose.

}, keywords = {DNA Fingerprinting, Eye Color, Forensic Genetics, Genetic Markers, Genotype, Hair Color, High-Throughput Nucleotide Sequencing, Humans, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Skin Pigmentation, Software}, issn = {2073-4425}, doi = {10.3390/genes11060708}, author = {Palencia-Madrid, Leire and Xavier, Catarina and de la Puente, Mar{\'\i}a and Hohoff, Carsten and Phillips, Christopher and Kayser, Manfred and Parson, Walther} } @article {89, title = {Genetic diagnoses in epilepsy: The impact of dynamic exome analysis in a pediatric cohort.}, journal = {Epilepsia}, volume = {61}, year = {2020}, month = {2020 02}, pages = {249-258}, abstract = {

OBJECTIVE: We evaluated the yield of systematic analysis and/or reanalysis of whole exome sequencing (WES) data from a cohort of well-phenotyped pediatric patients with epilepsy and suspected but previously undetermined genetic etiology.

METHODS: We identified and phenotyped 125 participants with pediatric epilepsy. Etiology was unexplained at the time of enrollment despite clinical testing, which included chromosomal microarray (57 patients), epilepsy gene panel (n = 48), both (n = 28), or WES (n = 8). Clinical epilepsy diagnoses included developmental and epileptic encephalopathy (DEE), febrile infection-related epilepsy syndrome, Rasmussen encephalitis, and other focal and generalized epilepsies. We analyzed WES data and compared the yield in participants with and without prior clinical genetic testing.

RESULTS: Overall, we identified pathogenic or likely pathogenic variants in 40\% (50/125) of our study participants. Nine patients with DEE had genetic variants in recently published genes that had not been recognized as epilepsy-related at the time of clinical testing (FGF12, GABBR1, GABBR2, ITPA, KAT6A, PTPN23, RHOBTB2, SATB2), and eight patients had genetic variants in candidate epilepsy genes (CAMTA1, FAT3, GABRA6, HUWE1, PTCHD1). Ninety participants had concomitant or subsequent clinical genetic testing, which was ultimately explanatory for 26\% (23/90). Of the 67 participants whose molecular diagnoses were "unsolved" through clinical genetic testing, we identified pathogenic or likely pathogenic variants in 17 (25\%).

SIGNIFICANCE: Our data argue for early consideration of WES with iterative reanalysis for patients with epilepsy, particularly those with DEE or epilepsy with intellectual disability. Rigorous analysis of WES data of well-phenotyped patients with epilepsy leads to a broader understanding of gene-specific phenotypic spectra as well as candidate disease gene identification. We illustrate the dynamic nature of genetic diagnosis over time, with analysis and in some cases reanalysis of exome data leading to the identification of disease-associated variants among participants with previously nondiagnostic results from a variety of clinical testing strategies.

}, keywords = {Adolescent, Adult, Age of Onset, Brain Diseases, Child, Child, Preschool, Chromosomes, Human, Cohort Studies, Epilepsy, Epilepsy, Generalized, Exome, Female, Genetic Testing, Genetic Variation, Humans, Infant, Male, Microarray Analysis, Phenotype, Whole Exome Sequencing, Young Adult}, issn = {1528-1167}, doi = {10.1111/epi.16427}, author = {Rochtus, Anne and Olson, Heather E and Smith, Lacey and Keith, Louisa G and El Achkar, Christelle and Taylor, Alan and Mahida, Sonal and Park, Meredith and Kelly, McKenna and Shain, Catherine and Rockowitz, Shira and Rosen Sheidley, Beth and Poduri, Annapurna} } @article {92, title = {Genetics of schizophrenia in the South African Xhosa.}, journal = {Science}, volume = {367}, year = {2020}, month = {2020 01 31}, pages = {569-573}, abstract = {

Africa, the ancestral home of all modern humans, is the most informative continent for understanding the human genome and its contribution to complex disease. To better understand the genetics of schizophrenia, we studied the illness in the Xhosa population of South Africa, recruiting 909 cases and 917 age-, gender-, and residence-matched controls. Individuals with schizophrenia were significantly more likely than controls to harbor private, severely damaging mutations in genes that are critical to synaptic function, including neural circuitry mediated by the neurotransmitters glutamine, γ-aminobutyric acid, and dopamine. Schizophrenia is genetically highly heterogeneous, involving severe ultrarare mutations in genes that are critical to synaptic plasticity. The depth of genetic variation in Africa revealed this relationship with a moderate sample size and informed our understanding of the genetics of schizophrenia worldwide.

}, keywords = {Age Factors, Autistic Disorder, Bipolar Disorder, Dopamine, Female, gamma-Aminobutyric Acid, Genetic Variation, Glutamine, Humans, Male, Mutation, Neural Pathways, Schizophrenia, Sex Factors, South Africa, Synapses, Synaptic Transmission}, issn = {1095-9203}, doi = {10.1126/science.aay8833}, author = {Gulsuner, S and Stein, D J and Susser, E S and Sibeko, G and Pretorius, A and Walsh, T and Majara, L and Mndini, M M and Mqulwana, S G and Ntola, O A and Casadei, S and Ngqengelele, L L and Korchina, V and van der Merwe, C and Malan, M and Fader, K M and Feng, M and Willoughby, E and Muzny, D and Baldinger, A and Andrews, H F and Gur, R C and Gibbs, R A and Zingela, Z and Nagdee, M and Ramesar, R S and King, M-C and McClellan, J M} } @article {104, title = {Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease.}, journal = {BMC Med Genomics}, volume = {13}, year = {2020}, month = {2020 08 26}, pages = {120}, abstract = {

BACKGROUND: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD.

METHODS: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.

RESULTS: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P~< 5 {\texttimes} 10), (ii) one previously suggested locus with experiment-wise significance (P~< 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism).

CONCLUSIONS: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

}, keywords = {Case-Control Studies, Genetic Loci, Genetic Markers, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Macular Degeneration, Polymorphism, Single Nucleotide}, issn = {1755-8794}, doi = {10.1186/s12920-020-00760-7}, author = {Winkler, Thomas W and Grassmann, Felix and Brandl, Caroline and Kiel, Christina and G{\"u}nther, Felix and Strunz, Tobias and Weidner, Lorraine and Zimmermann, Martina E and Korb, Christina A and Poplawski, Alicia and Schuster, Alexander K and M{\"u}ller-Nurasyid, Martina and Peters, Annette and Rauscher, Franziska G and Elze, Tobias and Horn, Katrin and Scholz, Markus and Ca{\~n}adas-Garre, Marisa and McKnight, Amy Jayne and Quinn, Nicola and Hogg, Ruth E and K{\"u}chenhoff, Helmut and Heid, Iris M and Stark, Klaus J and Weber, Bernhard H F} } @article {129, title = {Genome-Wide Polygenic Score, Clinical Risk Factors, and Long-Term Trajectories of Coronary Artery Disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {40}, year = {2020}, month = {2020 11}, pages = {2738-2746}, abstract = {

OBJECTIVE: To determine the relationship of a genome-wide polygenic score for coronary artery disease (GPS) with lifetime trajectories of CAD risk, directly compare its predictive capacity to traditional risk factors, and assess its interplay with the Pooled Cohort Equations (PCE) clinical risk estimator. Approach and Results: We studied GPS in 28 556 middle-aged participants of the Malm{\"o} Diet and Cancer Study, of whom 4122 (14.4\%) developed CAD over a median follow-up of 21.3 years. A pronounced gradient in lifetime risk of CAD was observed-16\% for those in the lowest GPS decile to 48\% in the highest. We evaluated the discriminative capacity of the GPS-as assessed by change in the C-statistic from a baseline model including age and sex-among 5685 individuals with PCE risk estimates available. The increment for the GPS (+0.045, <0.001) was higher than for any of 11 traditional risk factors (range +0.007 to +0.032). Minimal correlation was observed between GPS and 10-year risk defined by the PCE (=0.03), and addition of GPS improved the C-statistic of the PCE model by 0.026. A significant gradient in lifetime risk was observed for the GPS, even among individuals within a given PCE clinical risk stratum. We replicated key findings-noting strikingly consistent results-in 325 003 participants of the UK Biobank.

CONCLUSIONS: GPS-a risk estimator available from birth-stratifies individuals into varying trajectories of clinical risk for CAD. Implementation of GPS may enable identification of high-risk individuals early in life, decades in advance of manifest risk factors or disease.

}, keywords = {Adult, Aged, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Heart Disease Risk Factors, Heredity, Humans, Incidence, Male, Middle Aged, Multifactorial Inheritance, Phenotype, Prognosis, Risk Assessment, Sweden, Time Factors, United Kingdom}, issn = {1524-4636}, doi = {10.1161/ATVBAHA.120.314856}, author = {Hindy, George and Aragam, Krishna G and Ng, Kenney and Chaffin, Mark and Lotta, Luca A and Baras, Aris and Drake, Isabel and Orho-Melander, Marju and Melander, Olle and Kathiresan, Sekar and Khera, Amit V} } @article {130, title = {Heterozygous Gene Deficiency and Risk of Coronary Artery Disease.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 10}, pages = {417-423}, abstract = {

BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1\% in or .

RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1\% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95\% CI, 14-35]; =1.1{\texttimes}10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95\% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002871}, author = {Nomura, Akihiro and Emdin, Connor A and Won, Hong Hee and Peloso, Gina M and Natarajan, Pradeep and Ardissino, Diego and Danesh, John and Schunkert, Heribert and Correa, Adolfo and Bown, Matthew J and Samani, Nilesh J and Erdmann, Jeanette and McPherson, Ruth and Watkins, Hugh and Saleheen, Danish and Elosua, Roberto and Kawashiri, Masa-Aki and Tada, Hayato and Gupta, Namrata and Shah, Svati H and Rader, Daniel J and Gabriel, Stacey and Khera, Amit V and Kathiresan, Sekar} } @article {102, title = {The impact of sex on gene expression across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37\% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

}, keywords = {Chromosomes, Human, X, Disease, Epigenesis, Genetic, Female, Gene Expression, Gene Expression Regulation, Genetic Variation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Promoter Regions, Genetic, Quantitative Trait Loci, Sex Characteristics, Sex Factors}, issn = {1095-9203}, doi = {10.1126/science.aba3066}, author = {Oliva, Meritxell and Mu{\~n}oz-Aguirre, Manuel and Kim-Hellmuth, Sarah and Wucher, Valentin and Gewirtz, Ariel D H and Cotter, Daniel J and Parsana, Princy and Kasela, Silva and Balliu, Brunilda and Vi{\~n}uela, Ana and Castel, Stephane E and Mohammadi, Pejman and Aguet, Fran{\c c}ois and Zou, Yuxin and Khramtsova, Ekaterina A and Skol, Andrew D and Garrido-Mart{\'\i}n, Diego and Reverter, Ferran and Brown, Andrew and Evans, Patrick and Gamazon, Eric R and Payne, Anthony and Bonazzola, Rodrigo and Barbeira, Alvaro N and Hamel, Andrew R and Martinez-Perez, Angel and Soria, Jos{\'e} Manuel and Pierce, Brandon L and Stephens, Matthew and Eskin, Eleazar and Dermitzakis, Emmanouil T and Segr{\`e}, Ayellet V and Im, Hae Kyung and Engelhardt, Barbara E and Ardlie, Kristin G and Montgomery, Stephen B and Battle, Alexis J and Lappalainen, Tuuli and Guigo, Roderic and Stranger, Barbara E} } @article {120, title = {Inherited causes of clonal haematopoiesis in 97,691 whole genomes.}, journal = {Nature}, volume = {586}, year = {2020}, month = {2020 10}, pages = {763-768}, abstract = {

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is~termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP~driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

}, keywords = {Adult, Africa, African Continental Ancestry Group, Aged, Aged, 80 and over, alpha Karyopherins, Cell Self Renewal, Clonal Hematopoiesis, DNA-Binding Proteins, Female, Genetic Predisposition to Disease, Genome, Human, Germ-Line Mutation, Hematopoietic Stem Cells, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, National Heart, Lung, and Blood Institute (U.S.), Phenotype, Precision Medicine, Proto-Oncogene Proteins, Tripartite Motif Proteins, United States, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2819-2}, author = {Bick, Alexander G and Weinstock, Joshua S and Nandakumar, Satish K and Fulco, Charles P and Bao, Erik L and Zekavat, Seyedeh M and Szeto, Mindy D and Liao, Xiaotian and Leventhal, Matthew J and Nasser, Joseph and Chang, Kyle and Laurie, Cecelia and Burugula, Bala Bharathi and Gibson, Christopher J and Lin, Amy E and Taub, Margaret A and Aguet, Fran{\c c}ois and Ardlie, Kristin and Mitchell, Braxton D and Barnes, Kathleen C and Moscati, Arden and Fornage, Myriam and Redline, Susan and Psaty, Bruce M and Silverman, Edwin K and Weiss, Scott T and Palmer, Nicholette D and Vasan, Ramachandran S and Burchard, Esteban G and Kardia, Sharon L R and He, Jiang and Kaplan, Robert C and Smith, Nicholas L and Arnett, Donna K and Schwartz, David A and Correa, Adolfo and de Andrade, Mariza and Guo, Xiuqing and Konkle, Barbara A and Custer, Brian and Peralta, Juan M and Gui, Hongsheng and Meyers, Deborah A and McGarvey, Stephen T and Chen, Ida Yii-Der and Shoemaker, M Benjamin and Peyser, Patricia A and Broome, Jai G and Gogarten, Stephanie M and Wang, Fei Fei and Wong, Quenna and Montasser, May E and Daya, Michelle and Kenny, Eimear E and North, Kari E and Launer, Lenore J and Cade, Brian E and Bis, Joshua C and Cho, Michael H and Lasky-Su, Jessica and Bowden, Donald W and Cupples, L Adrienne and Mak, Angel C Y and Becker, Lewis C and Smith, Jennifer A and Kelly, Tanika N and Aslibekyan, Stella and Heckbert, Susan R and Tiwari, Hemant K and Yang, Ivana V and Heit, John A and Lubitz, Steven A and Johnsen, Jill M and Curran, Joanne E and Wenzel, Sally E and Weeks, Daniel E and Rao, Dabeeru C and Darbar, Dawood and Moon, Jee-Young and Tracy, Russell P and Buth, Erin J and Rafaels, Nicholas and Loos, Ruth J F and Durda, Peter and Liu, Yongmei and Hou, Lifang and Lee, Jiwon and Kachroo, Priyadarshini and Freedman, Barry I and Levy, Daniel and Bielak, Lawrence F and Hixson, James E and Floyd, James S and Whitsel, Eric A and Ellinor, Patrick T and Irvin, Marguerite R and Fingerlin, Tasha E and Raffield, Laura M and Armasu, Sebastian M and Wheeler, Marsha M and Sabino, Ester C and Blangero, John and Williams, L Keoki and Levy, Bruce D and Sheu, Wayne Huey-Herng and Roden, Dan M and Boerwinkle, Eric and Manson, JoAnn E and Mathias, Rasika A and Desai, Pinkal and Taylor, Kent D and Johnson, Andrew D and Auer, Paul L and Kooperberg, Charles and Laurie, Cathy C and Blackwell, Thomas W and Smith, Albert V and Zhao, Hongyu and Lange, Ethan and Lange, Leslie and Rich, Stephen S and Rotter, Jerome I and Wilson, James G and Scheet, Paul and Kitzman, Jacob O and Lander, Eric S and Engreitz, Jesse M and Ebert, Benjamin L and Reiner, Alexander P and Jaiswal, Siddhartha and Abecasis, Gon{\c c}alo and Sankaran, Vijay G and Kathiresan, Sekar and Natarajan, Pradeep} } @article {93, title = {Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism.}, journal = {Cell}, volume = {180}, year = {2020}, month = {2020 02 06}, pages = {568-584.e23}, abstract = {

We present the largest exome sequencing study of autism spectrum disorder (ASD) to date (n~= 35,584 total samples, 11,986 with ASD). Using an enhanced analytical framework to integrate de novo and case-control rare variation, we identify 102 risk genes at a false discovery rate of 0.1 or less. Of these genes, 49 show higher frequencies of disruptive de novo variants in individuals ascertained to have severe neurodevelopmental delay, whereas 53 show higher frequencies in individuals ascertained to have ASD; comparing ASD cases with mutations in these groups reveals phenotypic differences. Expressed early in brain development, most risk genes have roles in regulation of gene expression or neuronal communication (i.e., mutations effect neurodevelopmental and neurophysiological changes), and 13 fall within loci recurrently hit by copy number variants. In cells from the human cortex, expression of risk genes is enriched in excitatory and inhibitory neuronal lineages, consistent with multiple paths to an excitatory-inhibitory imbalance underlying ASD.

}, keywords = {Autistic Disorder, Case-Control Studies, Cell Lineage, Cerebral Cortex, Cohort Studies, Exome, Female, Gene Expression Regulation, Developmental, Gene Frequency, Genetic Predisposition to Disease, Humans, Male, Mutation, Missense, Neurobiology, Neurons, Phenotype, Sex Factors, Single-Cell Analysis, Whole Exome Sequencing}, issn = {1097-4172}, doi = {10.1016/j.cell.2019.12.036}, author = {Satterstrom, F Kyle and Kosmicki, Jack A and Wang, Jiebiao and Breen, Michael S and De Rubeis, Silvia and An, Joon-Yong and Peng, Minshi and Collins, Ryan and Grove, Jakob and Klei, Lambertus and Stevens, Christine and Reichert, Jennifer and Mulhern, Maureen S and Artomov, Mykyta and Gerges, Sherif and Sheppard, Brooke and Xu, Xinyi and Bhaduri, Aparna and Norman, Utku and Brand, Harrison and Schwartz, Grace and Nguyen, Rachel and Guerrero, Elizabeth E and Dias, Caroline and Betancur, Catalina and Cook, Edwin H and Gallagher, Louise and Gill, Michael and Sutcliffe, James S and Thurm, Audrey and Zwick, Michael E and B{\o}rglum, Anders D and State, Matthew W and Cicek, A Ercument and Talkowski, Michael E and Cutler, David J and Devlin, Bernie and Sanders, Stephan J and Roeder, Kathryn and Daly, Mark J and Buxbaum, Joseph D} } @article {118, title = {Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction.}, journal = {Genetics}, volume = {215}, year = {2020}, month = {2020 07}, pages = {869-886}, abstract = {

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 {\texttimes} 10, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.

}, issn = {1943-2631}, doi = {10.1534/genetics.120.303231}, author = {Mak, Angel C Y and Sajuthi, Satria and Joo, Jaehyun and Xiao, Shujie and Sleiman, Patrick M and White, Marquitta J and Lee, Eunice Y and Saef, Benjamin and Hu, Donglei and Gui, Hongsheng and Keys, Kevin L and Lurmann, Fred and Jain, Deepti and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Winterkorn, Lara and Reeves, Catherine and Huntsman, Scott and Eng, Celeste and Salazar, Sandra and Oh, Sam S and Gilliland, Frank D and Chen, Zhanghua and Kumar, Rajesh and Mart{\'\i}nez, Fernando D and Wu, Ann Chen and Ziv, Elad and Hakonarson, Hakon and Himes, Blanca E and Williams, L Keoki and Seibold, Max A and Burchard, Esteban G} } @article {112, title = {Major Impacts of Widespread Structural Variation on Gene Expression and Crop Improvement in Tomato.}, journal = {Cell}, volume = {182}, year = {2020}, month = {2020 07 09}, pages = {145-161.e23}, abstract = {

Structural variants (SVs) underlie important crop improvement and domestication traits. However, resolving the extent, diversity, and quantitative impact of SVs has been challenging. We used long-read nanopore sequencing to capture 238,490 SVs in 100 diverse tomato lines. This panSV genome, along with 14 new reference assemblies, revealed large-scale intermixing of diverse genotypes, as well as thousands of SVs intersecting genes and cis-regulatory regions. Hundreds of SV-gene pairs exhibit subtle and significant expression changes, which could broadly influence quantitative trait variation. By combining quantitative genetics with genome editing, we show how multiple SVs that changed gene dosage and expression levels modified fruit flavor, size, and production. In the last example, higher order epistasis among four SVs affecting three related transcription factors allowed introduction of an important harvesting trait in modern tomato. Our findings highlight the underexplored role of SVs in genotype-to-phenotype relationships and their widespread importance and utility in crop improvement.

}, keywords = {Alleles, Crops, Agricultural, Cytochrome P-450 Enzyme System, Ecotype, Epistasis, Genetic, Fruit, Gene Duplication, Gene Expression Regulation, Plant, Genome, Plant, Genomic Structural Variation, Genotype, Inbreeding, Lycopersicon esculentum, Molecular Sequence Annotation, Phenotype, Plant Breeding, Quantitative Trait Loci}, issn = {1097-4172}, doi = {10.1016/j.cell.2020.05.021}, author = {Alonge, Michael and Wang, Xingang and Benoit, Matthias and Soyk, Sebastian and Pereira, Lara and Zhang, Lei and Suresh, Hamsini and Ramakrishnan, Srividya and Maumus, Florian and Ciren, Danielle and Levy, Yuval and Harel, Tom Hai and Shalev-Schlosser, Gili and Amsellem, Ziva and Razifard, Hamid and Caicedo, Ana L and Tieman, Denise M and Klee, Harry and Kirsche, Melanie and Aganezov, Sergey and Ranallo-Benavidez, T Rhyker and Lemmon, Zachary H and Kim, Jennifer and Robitaille, Gina and Kramer, Melissa and Goodwin, Sara and McCombie, W Richard and Hutton, Samuel and Van Eck, Joyce and Gillis, Jesse and Eshed, Yuval and Sedlazeck, Fritz J and van der Knaap, Esther and Schatz, Michael C and Lippman, Zachary B} } @article {122, title = {Mapping and characterization of structural variation in 17,795 human genomes.}, journal = {Nature}, volume = {583}, year = {2020}, month = {2020 07}, pages = {83-89}, abstract = {

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0-11.2\% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2\% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90\% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2\% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.

}, keywords = {Alleles, Case-Control Studies, Continental Population Groups, Epigenesis, Genetic, Female, Gene Dosage, Genetic Variation, Genetics, Population, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Male, Molecular Sequence Annotation, Quantitative Trait Loci, Software, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2371-0}, author = {Abel, Haley J and Larson, David E and Regier, Allison A and Chiang, Colby and Das, Indraniel and Kanchi, Krishna L and Layer, Ryan M and Neale, Benjamin M and Salerno, William J and Reeves, Catherine and Buyske, Steven and Matise, Tara C and Muzny, Donna M and Zody, Michael C and Lander, Eric S and Dutcher, Susan K and Stitziel, Nathan O and Hall, Ira M} } @article {131, title = {A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease.}, journal = {PLoS Genet}, volume = {16}, year = {2020}, month = {2020 04}, pages = {e1008629}, abstract = {

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

}, keywords = {Alleles, Cholesterol, LDL, Coronary Artery Disease, Datasets as Topic, Fatty Liver, Female, Genetic Predisposition to Disease, Homozygote, Humans, Liver, Liver Cirrhosis, Liver Cirrhosis, Alcoholic, Loss of Function Mutation, Male, Middle Aged, Mitochondrial Proteins, Mutation, Missense, Oxidoreductases}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1008629}, author = {Emdin, Connor A and Haas, Mary E and Khera, Amit V and Aragam, Krishna and Chaffin, Mark and Klarin, Derek and Hindy, George and Jiang, Lan and Wei, Wei-Qi and Feng, Qiping and Karjalainen, Juha and Havulinna, Aki and Kiiskinen, Tuomo and Bick, Alexander and Ardissino, Diego and Wilson, James G and Schunkert, Heribert and McPherson, Ruth and Watkins, Hugh and Elosua, Roberto and Bown, Matthew J and Samani, Nilesh J and Baber, Usman and Erdmann, Jeanette and Gupta, Namrata and Danesh, John and Saleheen, Danish and Chang, Kyong-Mi and Vujkovic, Marijana and Voight, Ben and Damrauer, Scott and Lynch, Julie and Kaplan, David and Serper, Marina and Tsao, Philip and Mercader, Josep and Hanis, Craig and Daly, Mark and Denny, Joshua and Gabriel, Stacey and Kathiresan, Sekar} } @article {96, title = {Neurophysiological and Genetic Findings in Patients With Juvenile Myoclonic Epilepsy.}, journal = {Front Integr Neurosci}, volume = {14}, year = {2020}, month = {2020}, pages = {45}, abstract = {

Objective: Transcranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia.

Methods: 20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10-15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied.

Results: We identified increased polyphasia in patients (85\%) and relatives (70\%) compared to controls (47\%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in , in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia.

Conclusion: Polyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives.

}, issn = {1662-5145}, doi = {10.3389/fnint.2020.00045}, author = {Stefani, Stefani and Kousiappa, Ioanna and Nicolaou, Nicoletta and Papathanasiou, Eleftherios S and Oulas, Anastasis and Fanis, Pavlos and Neocleous, Vassos and Phylactou, Leonidas A and Spyrou, George M and Papacostas, Savvas S} } @article {141, title = {Non-parametric Polygenic Risk Prediction via Partitioned GWAS Summary Statistics.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 07 02}, pages = {46-59}, abstract = {

In complex trait genetics, the ability to predict phenotype from genotype is the ultimate measure of our understanding of genetic architecture underlying the heritability of a trait. A complete understanding of the genetic basis of a trait should allow for predictive methods with accuracies approaching the trait{\textquoteright}s heritability. The highly polygenic nature of quantitative traits and most common phenotypes has motivated the development of statistical strategies focused on combining myriad individually non-significant genetic effects. Now that predictive accuracies are improving, there is a growing interest in the practical utility of such methods for predicting risk of common diseases responsive to early therapeutic intervention. However, existing methods require individual-level genotypes or depend on accurately specifying the genetic architecture underlying each disease to be predicted. Here, we propose a polygenic risk prediction method that does not require explicitly modeling any underlying genetic architecture. We start with summary statistics in the form of SNP effect sizes from a large GWAS cohort. We then remove the correlation structure across summary statistics arising due to linkage disequilibrium and apply a piecewise linear interpolation on conditional mean effects. In both simulated and real datasets, this new non-parametric shrinkage (NPS) method can reliably allow for linkage disequilibrium in summary statistics of 5 million dense genome-wide markers and consistently improves prediction accuracy. We show that NPS improves the identification of groups at high risk for breast cancer, type 2 diabetes, inflammatory bowel disease, and coronary heart disease, all of which have available early intervention or prevention treatments.

}, keywords = {Aged, Cohort Studies, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Genotype, Humans, Linkage Disequilibrium, Male, Middle Aged, Models, Genetic, Multifactorial Inheritance, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.05.004}, author = {Chun, Sung and Imakaev, Maxim and Hui, Daniel and Patsopoulos, Nikolaos A and Neale, Benjamin M and Kathiresan, Sekar and Stitziel, Nathan O and Sunyaev, Shamil R} } @article {125, title = {The Parkinson{\textquoteright}s Disease Genome-Wide Association Study Locus Browser.}, journal = {Mov Disord}, volume = {35}, year = {2020}, month = {2020 11}, pages = {2056-2067}, abstract = {

BACKGROUND: Parkinson{\textquoteright}s disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome-wide association studies. The most recent large-scale PD genome-wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome-wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus.

METHODS: We included all significant genome-wide signals from multiple recent PD genome-wide association studies including themost recent PD risk genome-wide association study, age-at-onset genome-wide association study, progression genome-wide association study, and Asian population PD risk genome-wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Multiple databases were queried for each gene to collect additional causal data.

RESULTS: We created a PD genome-wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow-up functional studies to identify potential therapeutic targets.

CONCLUSIONS: Our PD genome-wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large-scale PD genome-wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. {\textcopyright} 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

}, keywords = {Age of Onset, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Neurodegenerative Diseases, Parkinson Disease, Risk Factors}, issn = {1531-8257}, doi = {10.1002/mds.28197}, author = {Grenn, Francis P and Kim, Jonggeol J and Makarious, Mary B and Iwaki, Hirotaka and Illarionova, Anastasia and Brolin, Kajsa and Kluss, Jillian H and Schumacher-Schuh, Artur F and Leonard, Hampton and Faghri, Faraz and Billingsley, Kimberley and Krohn, Lynne and Hall, Ashley and Diez-Fairen, Monica and Peri{\~n}{\'a}n, Maria Teresa and Foo, Jia Nee and Sandor, Cynthia and Webber, Caleb and Fiske, Brian K and Gibbs, J Raphael and Nalls, Mike A and Singleton, Andrew B and Bandres-Ciga, Sara and Reed, Xylena and Blauwendraat, Cornelis} } @article {135, title = {Parliament2: Accurate structural variant calling at scale.}, journal = {Gigascience}, volume = {9}, year = {2020}, month = {2020 12 21}, abstract = {

BACKGROUND: Structural variants (SVs) are critical contributors to genetic diversity and genomic disease. To predict the phenotypic impact of SVs, there is a need for better estimates of both the occurrence and frequency of SVs, preferably from large, ethnically diverse cohorts. Thus, the current standard approach requires the use of short paired-end reads, which remain challenging to detect, especially at the scale of hundreds to thousands of samples.

FINDINGS: We present Parliament2, a consensus SV framework that leverages multiple best-in-class methods to identify high-quality SVs from short-read DNA sequence data at scale. Parliament2 incorporates pre-installed SV callers that are optimized for efficient execution in parallel to reduce the overall runtime and costs. We demonstrate the accuracy of Parliament2 when applied to data from NovaSeq and HiSeq X platforms with the Genome in a Bottle (GIAB) SV call set across all size classes. The reported quality score per SV is calibrated across different SV types and size classes. Parliament2 has the highest F1 score (74.27\%) measured across the independent gold standard from GIAB. We illustrate the compute performance by processing all 1000 Genomes samples (2,691 samples) in <1 day on GRCH38. Parliament2 improves the runtime performance of individual methods and is open source (https://github.com/slzarate/parliament2), and a Docker image, as well as a WDL implementation, is available.

CONCLUSION: Parliament2 provides both a highly accurate single-sample SV call set from short-read DNA sequence data and enables cost-efficient application over cloud or cluster environments, processing thousands of samples.

}, issn = {2047-217X}, doi = {10.1093/gigascience/giaa145}, author = {Zarate, Samantha and Carroll, Andrew and Mahmoud, Medhat and Krasheninina, Olga and Jun, Goo and Salerno, William J and Schatz, Michael C and Boerwinkle, Eric and Gibbs, Richard A and Sedlazeck, Fritz J} } @article {128, title = {Phenotypic expansion in KIF1A-related dominant disorders: A description of novel variants and review of published cases.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 12}, pages = {2094-2104}, abstract = {

KIF1A is a molecular motor for membrane-bound cargo important to the development and survival of sensory neurons. KIF1A dysfunction has been associated with several Mendelian disorders with a spectrum of overlapping phenotypes, ranging from spastic paraplegia to intellectual disability. We present a novel pathogenic in-frame deletion in the KIF1A molecular motor domain inherited by two affected siblings from an unaffected mother with apparent germline mosaicism. We identified eight additional cases with heterozygous, pathogenic KIF1A variants ascertained from a local data lake. Our data provide evidence for the expansion of KIF1A-associated phenotypes to include hip subluxation and dystonia~as well as phenotypes observed in only a single case: gelastic cataplexy, coxa valga, and double collecting system. We review the literature and suggest that KIF1A dysfunction is better understood as a single neuromuscular disorder with variable involvement of other organ systems than a set of discrete disorders converging at a single locus.

}, issn = {1098-1004}, doi = {10.1002/humu.24118}, author = {Montenegro-Garreaud, Ximena and Hansen, Adam W and Khayat, Michael M and Chander, Varuna and Grochowski, Christopher M and Jiang, Yunyun and Li, He and Mitani, Tadahiro and Kessler, Elena and Jayaseelan, Joy and Shen, Hua and Gezdirici, Alper and Pehlivan, Davut and Meng, Qingchang and Rosenfeld, Jill A and Jhangiani, Shalini N and Madan-Khetarpal, Suneeta and Scott, Daryl A and Abarca-Barriga, Hugo and Trubnykova, Milana and Gingras, Marie-Claude and Muzny, Donna M and Posey, Jennifer E and Liu, Pengfei and Lupski, James R and Gibbs, Richard A} } @article {105, title = {Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 08 20}, pages = {3635}, abstract = {

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17\% to 78\% for coronary artery disease, 13\% to 76\% for breast cancer, and 11\% to 80\% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

}, keywords = {Aged, Breast Neoplasms, Case-Control Studies, Colorectal Neoplasms, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genome, Human, Humans, Male, Middle Aged, Multifactorial Inheritance, Odds Ratio, Penetrance, Risk Factors}, issn = {2041-1723}, doi = {10.1038/s41467-020-17374-3}, author = {Fahed, Akl C and Wang, Minxian and Homburger, Julian R and Patel, Aniruddh P and Bick, Alexander G and Neben, Cynthia L and Lai, Carmen and Brockman, Deanna and Philippakis, Anthony and Ellinor, Patrick T and Cassa, Christopher A and Lebo, Matthew and Ng, Kenney and Lander, Eric S and Zhou, Alicia Y and Kathiresan, Sekar and Khera, Amit V} } @article {91, title = {Rapid, Paralog-Sensitive CNV Analysis of 2457 Human Genomes Using QuicK-mer2.}, journal = {Genes (Basel)}, volume = {11}, year = {2020}, month = {2020 01 29}, abstract = {

Gene duplication is a major mechanism for the evolution of gene novelty, and copy-number variation makes a major contribution to inter-individual genetic diversity. However, most approaches for studying copy-number variation rely upon uniquely mapping reads to a genome reference and are unable to distinguish among duplicated sequences. Specialized approaches to interrogate specific paralogs are comparatively slow and have a high degree of computational complexity, limiting their effective application to emerging population-scale data sets. We present QuicK-mer2, a self-contained, mapping-free approach that enables the rapid construction of paralog-specific copy-number maps from short-read sequence data. This approach is based on the tabulation of unique k-mer sequences from short-read data sets, and is able to analyze a 20X coverage human genome in approximately 20 min. We applied our approach to newly released sequence data from the 1000 Genomes Project, constructed paralog-specific copy-number maps from 2457 unrelated individuals, and uncovered copy-number variation of paralogous genes. We identify nine genes where none of the analyzed samples have a copy number of two, 92 genes where the majority of samples have a copy number other than two, and describe rare copy number variation effecting multiple genes at the APOBEC3 locus.

}, keywords = {Algorithms, Computational Biology, DNA Copy Number Variations, Evolution, Molecular, Gene Duplication, Genome, Human, Humans, Sequence Analysis, DNA}, issn = {2073-4425}, doi = {10.3390/genes11020141}, author = {Shen, Feichen and Kidd, Jeffrey M} } @article {113, title = {Serum sphingolipids and incident diabetes in a US population with high diabetes burden: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).}, journal = {Am J Clin Nutr}, volume = {112}, year = {2020}, month = {2020 07 01}, pages = {57-65}, abstract = {

BACKGROUND: Genetic or pharmacological inhibition of de novo sphingolipid synthases prevented diabetes in animal studies.

OBJECTIVES: We sought to evaluate prospective associations of serum sphingolipids with incident diabetes in a population-based cohort.

METHODS: We included 2010 participants of the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) aged 18-74 y who were free of diabetes and other major chronic diseases at baseline (2008-2011). Metabolomic profiling of fasting serum was performed using a global, untargeted approach. A total of 43 sphingolipids were quantified and, considering subclasses and chemical structures of individual species, 6 sphingolipid scores were constructed. Diabetes status was assessed using standard procedures including blood tests. Multivariable survey Poisson regressions were applied to estimate RR and 95\% CI of incident diabetes associated with individual sphingolipids or sphingolipid scores.

RESULTS: There were 224 incident cases of diabetes identified during, on average, 6 y of follow-up. After adjustment for socioeconomic and lifestyle factors, a ceramide score (RR Q4 versus Q1~=~2.40; 95\% CI: 1.24, 4.65; P-trend~=~0.003) and a score of sphingomyelins with fully saturated sphingoid-fatty acid pairs (RR Q4 versus Q1~=~3.15; 95\% CI: 1.75, 5.67; P-trend~<0.001) both were positively associated with risk of diabetes, whereas scores of glycosylceramides, lactosylceramides, or other unsaturated sphingomyelins (even if having an SFA base) were not associated with risk of diabetes. After additional adjustment for numerous traditional risk factors (especially triglycerides), both associations were attenuated and only the saturated-sphingomyelin score remained associated with risk of diabetes (RR Q4 versus Q1~=~1.98; 95\% CI: 1.09, 3.59; P-trend~=~0.031).

CONCLUSIONS: Our findings suggest that a cluster of saturated sphingomyelins may be associated with elevated risk of diabetes beyond traditional risk factors, which needs to be verified in other population studies. This study was registered at clinicaltrials.gov as NCT02060344.

}, keywords = {Adolescent, Adult, Aged, Diabetes Mellitus, Female, Hispanic Americans, Humans, Male, Middle Aged, Prospective Studies, Risk Factors, Sphingolipids, United States, Young Adult}, issn = {1938-3207}, doi = {10.1093/ajcn/nqaa114}, author = {Chen, Guo-Chong and Chai, Jin Choul and Yu, Bing and Michelotti, Gregory A and Grove, Megan L and Fretts, Amanda M and Daviglus, Martha L and Garcia-Bedoya, Olga L and Thyagarajan, Bharat and Schneiderman, Neil and Cai, Jianwen and Kaplan, Robert C and Boerwinkle, Eric and Qi, Qibin} } @article {94, title = {Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 05}, pages = {945-953}, abstract = {

PURPOSE: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics and Genomics.

METHODS: We developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2.

RESULTS: We characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses, and calculated a pan-ethnic carrier frequency of 2\%, consistent with previous studies. Additionally, 99.8\% of our SMN1 and 99.7\% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100\% for SMA and 97.8\% for carriers, and a precision of 100\% for both SMA and carriers.

CONCLUSION: This SMN copy-number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.

}, keywords = {Base Sequence, Child, Child, Preschool, Humans, Muscular Atrophy, Spinal, Survival of Motor Neuron 1 Protein}, issn = {1530-0366}, doi = {10.1038/s41436-020-0754-0}, author = {Chen, Xiao and Sanchis-Juan, Alba and French, Courtney E and Connell, Andrew J and Delon, Isabelle and Kingsbury, Zoya and Chawla, Aditi and Halpern, Aaron L and Taft, Ryan J and Bentley, David R and Butchbach, Matthew E R and Raymond, F Lucy and Eberle, Michael A} } @article {114, title = {A structural variation reference for medical and population genetics.}, journal = {Nature}, volume = {581}, year = {2020}, month = {2020 05}, pages = {444-451}, abstract = {

Structural variants (SVs) rearrange large segments of DNA and can have profound consequences in evolution and human disease. As national biobanks, disease-association studies, and clinical genetic testing have grown increasingly reliant on genome sequencing, population references such as the Genome Aggregation Database (gnomAD) have become integral in the interpretation of single-nucleotide variants (SNVs). However, there are no reference maps of SVs from high-coverage genome sequencing comparable to those for SNVs. Here we present a reference of sequence-resolved SVs constructed from 14,891 genomes across diverse global populations (54\% non-European) in gnomAD. We discovered a rich and complex landscape of 433,371 SVs, from which we estimate that SVs are responsible for 25-29\% of all rare protein-truncating events per genome. We found strong correlations between natural selection against damaging SNVs and rare SVs that disrupt or duplicate protein-coding sequence, which suggests that genes that are highly intolerant to loss-of-function are also sensitive to increased dosage. We also uncovered modest selection against noncoding SVs in cis-regulatory elements, although selection against protein-truncating SVs was stronger than all noncoding effects. Finally, we identified very large (over one megabase), rare SVs in 3.9\% of samples, and estimate that 0.13\% of individuals may carry an SV that meets the existing criteria for clinically important incidental findings. This SV resource is freely distributed via the gnomAD browser and will have broad utility in population genetics, disease-association studies, and diagnostic screening.

}, keywords = {Continental Population Groups, Disease, Female, Genetic Testing, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genotyping Techniques, Humans, Male, Middle Aged, Mutation, Polymorphism, Single Nucleotide, Reference Standards, Selection, Genetic, Whole Genome Sequencing}, issn = {1476-4687}, doi = {10.1038/s41586-020-2287-8}, author = {Collins, Ryan L and Brand, Harrison and Karczewski, Konrad J and Zhao, Xuefang and Alf{\"o}ldi, Jessica and Francioli, Laurent C and Khera, Amit V and Lowther, Chelsea and Gauthier, Laura D and Wang, Harold and Watts, Nicholas A and Solomonson, Matthew and O{\textquoteright}Donnell-Luria, Anne and Baumann, Alexander and Munshi, Ruchi and Walker, Mark and Whelan, Christopher W and Huang, Yongqing and Brookings, Ted and Sharpe, Ted and Stone, Matthew R and Valkanas, Elise and Fu, Jack and Tiao, Grace and Laricchia, Kristen M and Ruano-Rubio, Valentin and Stevens, Christine and Gupta, Namrata and Cusick, Caroline and Margolin, Lauren and Taylor, Kent D and Lin, Henry J and Rich, Stephen S and Post, Wendy S and Chen, Yii-Der Ida and Rotter, Jerome I and Nusbaum, Chad and Philippakis, Anthony and Lander, Eric and Gabriel, Stacey and Neale, Benjamin M and Kathiresan, Sekar and Daly, Mark J and Banks, Eric and MacArthur, Daniel G and Talkowski, Michael E} } @article {136, title = {Titin Truncating Variants in Adults Without Known Congestive Heart~Failure.}, journal = {J Am Coll Cardiol}, volume = {75}, year = {2020}, month = {2020 03 17}, pages = {1239-1241}, keywords = {Adult, Aged, Asymptomatic Diseases, Connectin, Female, Genetic Variation, Heart Failure, Humans, Male, Middle Aged}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.01.013}, author = {Pirruccello, James P and Bick, Alexander and Chaffin, Mark and Aragam, Krishna G and Choi, Seung Hoan and Lubitz, Steven A and Ho, Carolyn Y and Ng, Kenney and Philippakis, Anthony and Ellinor, Patrick T and Kathiresan, Sekar and Khera, Amit V} } @article {101, title = {Transcriptomic signatures across human tissues identify functional rare genetic variation.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, abstract = {

Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.

}, keywords = {Genetic Variation, Genome, Human, Humans, Multifactorial Inheritance, Organ Specificity, Transcriptome}, issn = {1095-9203}, doi = {10.1126/science.aaz5900}, author = {Ferraro, Nicole M and Strober, Benjamin J and Einson, Jonah and Abell, Nathan S and Aguet, Fran{\c c}ois and Barbeira, Alvaro N and Brandt, Margot and Bucan, Maja and Castel, Stephane E and Davis, Joe R and Greenwald, Emily and Hess, Gaelen T and Hilliard, Austin T and Kember, Rachel L and Kotis, Bence and Park, YoSon and Peloso, Gina and Ramdas, Shweta and Scott, Alexandra J and Smail, Craig and Tsang, Emily K and Zekavat, Seyedeh M and Ziosi, Marcello and Ardlie, Kristin G and Assimes, Themistocles L and Bassik, Michael C and Brown, Christopher D and Correa, Adolfo and Hall, Ira and Im, Hae Kyung and Li, Xin and Natarajan, Pradeep and Lappalainen, Tuuli and Mohammadi, Pejman and Montgomery, Stephen B and Battle, Alexis} } @article {123, title = {Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 10 12}, pages = {5139}, abstract = {

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

}, keywords = {Angiotensin-Converting Enzyme 2, Betacoronavirus, Child, Coronavirus Infections, COVID-19, Epithelial Cells, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Host-Pathogen Interactions, Humans, Inflammation, Interferons, Interleukin-13, Middle Aged, Nasal Mucosa, Pandemics, Peptidyl-Dipeptidase A, Pneumonia, Viral, SARS-CoV-2, Serine Endopeptidases, Virus Internalization}, issn = {2041-1723}, doi = {10.1038/s41467-020-18781-2}, author = {Sajuthi, Satria P and DeFord, Peter and Li, Yingchun and Jackson, Nathan D and Montgomery, Michael T and Everman, Jamie L and Rios, Cydney L and Pruesse, Elmar and Nolin, James D and Plender, Elizabeth G and Wechsler, Michael E and Mak, Angel C Y and Eng, Celeste and Salazar, Sandra and Medina, Vivian and Wohlford, Eric M and Huntsman, Scott and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Rice, Kenneth M and Kumar, Rajesh and Oh, Sam and Rodriguez-Santana, Jose and Burchard, Esteban G and Seibold, Max A} } @article {132, title = {Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium.}, journal = {bioRxiv}, year = {2020}, month = {2020 Apr 10}, abstract = {

Coronavirus disease 2019 (COVID-19) outcomes vary from asymptomatic infection to death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci (eQTL) for both and , that vary in frequency across world populations. Importantly, we find is part of a mucus secretory network, highly upregulated by T2 inflammation through the action of interleukin-13, and that interferon response to respiratory viruses highly upregulates expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate while also stimulating a more pronounced cytotoxic immune response relative to other respiratory viruses. Our results reveal mechanisms likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

}, doi = {10.1101/2020.04.09.034454}, author = {Sajuthi, Satria P and DeFord, Peter and Jackson, Nathan D and Montgomery, Michael T and Everman, Jamie L and Rios, Cydney L and Pruesse, Elmar and Nolin, James D and Plender, Elizabeth G and Wechsler, Michael E and Mak, Angel Cy and Eng, Celeste and Salazar, Sandra and Medina, Vivian and Wohlford, Eric M and Huntsman, Scott and Nickerson, Deborah A and Germer, Soren and Zody, Michael C and Abecasis, Gon{\c c}alo and Kang, Hyun Min and Rice, Kenneth M and Kumar, Rajesh and Oh, Sam and Rodriguez-Santana, Jose and Burchard, Esteban G and Seibold, Max A} } @article {127, title = {Validation of a Genome-Wide Polygenic~Score for Coronary Artery~Disease in~South Asians.}, journal = {J Am Coll Cardiol}, volume = {76}, year = {2020}, month = {2020 08 11}, pages = {703-714}, abstract = {

BACKGROUND: Genome-wide polygenic scores (GPS) integrate information from many common DNA variants into a single number. Because rates of coronary artery disease (CAD) are substantially higher among South Asians, a GPS to identify high-risk individuals may be particularly useful in this population.

OBJECTIVES: This analysis used summary statistics from a prior genome-wide association study to derive a new GPS for South Asians.

METHODS: This GPS was validated in 7,244 South Asian UK Biobank participants and tested in 491 individuals from a case-control study in Bangladesh. Next, a static ancestry and GPS reference distribution was built using whole-genome sequencing from 1,522 Indian individuals, and a framework was tested for projecting individuals onto this static ancestry and GPS reference distribution using 1,800 CAD cases and 1,163 control subjects newly recruited in India.

RESULTS: The GPS, containing 6,630,150 common DNA variants, had an odds ratio (OR) per SD of 1.58 in South Asian UK Biobank participants and 1.60 in the Bangladeshi study (p~<~0.001 for each). Next, individuals of the Indian case-control study were projected onto static reference distributions, observing an OR/SD of 1.66 (p~<~0.001). Compared with the middle quintile, risk for CAD was most pronounced for those in the top 5\% of the GPS distribution-ORs of 4.16, 2.46, and 3.22 in the South Asian UK Biobank, Bangladeshi, and Indian studies, respectively (p~<~0.05 for each).

CONCLUSIONS: The new GPS has been developed and tested using 3 distinct South Asian studies, and provides a generalizable framework for ancestry-specific GPS assessment.

}, keywords = {Adult, Aged, Bangladesh, Case-Control Studies, Coronary Artery Disease, Female, Genome-Wide Association Study, Humans, India, Male, Middle Aged, Multifactorial Inheritance}, issn = {1558-3597}, doi = {10.1016/j.jacc.2020.06.024}, author = {Wang, Minxian and Menon, Ramesh and Mishra, Sanghamitra and Patel, Aniruddh P and Chaffin, Mark and Tanneeru, Deepak and Deshmukh, Manjari and Mathew, Oshin and Apte, Sanika and Devanboo, Christina S and Sundaram, Sumathi and Lakshmipathy, Praveena and Murugan, Sakthivel and Sharma, Krishna Kumar and Rajendran, Karthikeyan and Santhosh, Sam and Thachathodiyl, Rajesh and Ahamed, Hisham and Balegadde, Aniketh Vijay and Alexander, Thomas and Swaminathan, Krishnan and Gupta, Rajeev and Mullasari, Ajit S and Sigamani, Alben and Kanchi, Muralidhar and Peterson, Andrew S and Butterworth, Adam S and Danesh, John and Di Angelantonio, Emanuele and Naheed, Aliya and Inouye, Michael and Chowdhury, Rajiv and Vedam, Ramprasad L and Kathiresan, Sekar and Gupta, Ravi and Khera, Amit V} } @article {121, title = {What Is Familial Hypercholesterolemia, and Why Does It Matter?}, journal = {Circulation}, volume = {141}, year = {2020}, month = {2020 06 02}, pages = {1760-1763}, keywords = {Atherosclerosis, Cardiovascular Diseases, Cholesterol, LDL, Humans, Hyperlipoproteinemia Type II, Prevalence}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.120.046961}, author = {Khera, Amit V and Hegele, Robert A} } @article {72, title = {Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Sep 05}, pages = {493-508}, abstract = {

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.07.007}, author = {Flex, Elisabetta and Martinelli, Simone and Van Dijck, Anke and Ciolfi, Andrea and Cecchetti, Serena and Coluzzi, Elisa and Pannone, Luca and Andreoli, Cristina and Radio, Francesca Clementina and Pizzi, Simone and Carpentieri, Giovanna and Bruselles, Alessandro and Catanzaro, Giuseppina and Pedace, Lucia and Miele, Evelina and Carcarino, Elena and Ge, Xiaoyan and Chijiwa, Chieko and Lewis, M E Suzanne and Meuwissen, Marije and Kenis, Sandra and Van der Aa, Nathalie and Larson, Austin and Brown, Kathleen and Wasserstein, Melissa P and Skotko, Brian G and Begtrup, Amber and Person, Richard and Karayiorgou, Maria and Roos, J Louw and Van Gassen, Koen L and Koopmans, Marije and Bijlsma, Emilia K and Santen, Gijs W E and Barge-Schaapveld, Daniela Q C M and Ruivenkamp, Claudia A L and Hoffer, Mariette J V and Lalani, Seema R and Streff, Haley and Craigen, William J and Graham, Brett H and van den Elzen, Annette P M and Kamphuis, Daan J and {\~O}unap, Katrin and Reinson, Karit and Pajusalu, Sander and Wojcik, Monica H and Viberti, Clara and Di Gaetano, Cornelia and Bertini, Enrico and Petrucci, Simona and De Luca, Alessandro and Rota, Rossella and Ferretti, Elisabetta and Matullo, Giuseppe and Dallapiccola, Bruno and Sgura, Antonella and Walkiewicz, Magdalena and Kooy, R Frank and Tartaglia, Marco} } @article {78, title = {Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome.}, journal = {Nat Biotechnol}, volume = {37}, year = {2019}, month = {2019 Oct}, pages = {1155-1162}, abstract = {

The DNA sequencing technologies in use today produce either highly accurate short reads or less-accurate long reads. We report the optimization of circular consensus sequencing (CCS) to improve the accuracy of single-molecule real-time (SMRT) sequencing (PacBio) and generate highly accurate (99.8\%) long high-fidelity (HiFi) reads with an average length of 13.5 kilobases (kb). We applied our approach to sequence the well-characterized human HG002/NA24385 genome and obtained precision and recall rates of at least 99.91\% for single-nucleotide variants (SNVs), 95.98\% for insertions and deletions <50 bp (indels) and 95.99\% for structural variants. Our CCS method matches or exceeds the ability of short-read sequencing to detect small variants and structural variants. We estimate that 2,434 discordances are correctable mistakes in the {\textquoteright}genome in a bottle{\textquoteright} (GIAB) benchmark set. Nearly all (99.64\%) variants can be phased into haplotypes, further improving variant detection. De novo genome assembly using CCS reads alone produced a contiguous and accurate genome with a contig N50 of >15 megabases (Mb) and concordance of 99.997\%, substantially outperforming assembly with less-accurate long reads.

}, issn = {1546-1696}, doi = {10.1038/s41587-019-0217-9}, author = {Wenger, Aaron M and Peluso, Paul and Rowell, William J and Chang, Pi-Chuan and Hall, Richard J and Concepcion, Gregory T and Ebler, Jana and Fungtammasan, Arkarachai and Kolesnikov, Alexey and Olson, Nathan D and T{\"o}pfer, Armin and Alonge, Michael and Mahmoud, Medhat and Qian, Yufeng and Chin, Chen-Shan and Phillippy, Adam M and Schatz, Michael C and Myers, Gene and DePristo, Mark A and Ruan, Jue and Marschall, Tobias and Sedlazeck, Fritz J and Zook, Justin M and Li, Heng and Koren, Sergey and Carroll, Andrew and Rank, David R and Hunkapiller, Michael W} } @article {76, title = {Biallelic and De Novo Variants in DONSON Reveal a Clinical Spectrum of Cell Cycle-opathies with Microcephaly, Dwarfism and Skeletal Abnormalities.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {2056-2066}, abstract = {

Co-occurrence of primordial dwarfism and microcephaly together with particular skeletal findings are seen in a wide range of Mendelian syndromes including microcephaly micromelia syndrome (MMS, OMIM 251230), microcephaly, short stature, and limb abnormalities (MISSLA, OMIM 617604), and microcephalic primordial dwarfisms (MPDs). Genes associated with these syndromes encode proteins that have crucial roles in DNA replication or in other critical steps of the cell cycle that link DNA replication to cell division. We identified four unrelated families with five affected individuals having biallelic or de novo variants in DONSON presenting with a core phenotype of severe short stature (z score < -3 SD), additional skeletal abnormalities, and microcephaly. Two apparently unrelated families with identical homozygous c.631C > T p.(Arg211Cys) variant had clinical features typical of Meier-Gorlin syndrome (MGS), while two siblings with compound heterozygous c.346delG p.(Asp116Ile*62) and c.1349A > G p.(Lys450Arg) variants presented with Seckel-like phenotype. We also identified a de novo c.683G > T p.(Trp228Leu) variant in DONSON in a patient with prominent micrognathia, short stature and hypoplastic femur and tibia, clinically diagnosed with Femoral-Facial syndrome (FFS, OMIM 134780). Biallelic variants in DONSON have been recently described in individuals with microcephalic dwarfism. These studies also demonstrated that DONSON has an essential conserved role in the cell cycle. Here we describe novel biallelic and de novo variants that are associated with MGS, Seckel-like phenotype and FFS, the last of which has not been associated with any disease gene to date.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61315}, author = {Karaca, Ender and Posey, Jennifer E and Bostwick, Bret and Liu, Pengfei and Gezdirici, Alper and Yesil, Gozde and Coban Akdemir, Zeynep and Bayram, Yavuz and Harms, Frederike L and Meinecke, Peter and Alawi, Malik and Bacino, Carlos A and Sutton, V Reid and Kort{\"u}m, Fanny and Lupski, James R} } @article {77, title = {Biallelic CACNA2D2 variants in epileptic encephalopathy and cerebellar atrophy.}, journal = {Ann Clin Transl Neurol}, volume = {6}, year = {2019}, month = {2019 Aug}, pages = {1395-1406}, abstract = {

OBJECTIVE: To characterize the molecular and clinical phenotypic basis of developmental and epileptic encephalopathies caused by rare biallelic variants in CACNA2D2.

METHODS: Two affected individuals from a family with clinical features of early onset epileptic encephalopathy were recruited for exome sequencing at the Centers for Mendelian Genomics to identify their molecular diagnosis. GeneMatcher facilitated identification of a second family with a shared candidate disease gene identified through clinical gene panel-based testing.

RESULTS: Rare biallelic CACNA2D2 variants have been previously reported in three families with developmental and epileptic encephalopathy, and one family with congenital ataxia. We identified three individuals in two unrelated families with novel homozygous rare variants in CACNA2D2 with clinical features of developmental and epileptic encephalopathy and cerebellar atrophy. Family 1 includes two affected siblings with a likely damaging homozygous rare missense variant c.1778G>C; p.(Arg593Pro) in CACNA2D2. Family 2 includes a proband with a homozygous rare nonsense variant c.485_486del; p.(Tyr162Ter) in CACNA2D2. We compared clinical and molecular findings from all nine individuals reported to date and note that cerebellar atrophy is shared among all.

INTERPRETATION: Our study supports the candidacy of CACNA2D2 as a disease gene associated with a phenotypic spectrum of neurological disease that include features of developmental and epileptic encephalopathy, ataxia, and cerebellar atrophy. Age at presentation may affect apparent penetrance of neurogenetic trait manifestations and of a particular clinical neurological endophenotype, for example, seizures or ataxia.

}, issn = {2328-9503}, doi = {10.1002/acn3.50824}, author = {Punetha, Jaya and Karaca, Ender and Gezdirici, Alper and Lamont, Ryan E and Pehlivan, Davut and Marafi, Dana and Appendino, Juan P and Hunter, Jill V and Akdemir, Zeynep C and Fatih, Jawid M and Jhangiani, Shalini N and Gibbs, Richard A and Innes, A Micheil and Posey, Jennifer E and Lupski, James R} } @article {75, title = {Bi-allelic GOT2 Mutations Cause a Treatable Malate-Aspartate Shuttle-Related Encephalopathy.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Sep 05}, pages = {534-548}, abstract = {

Early-infantile encephalopathies with epilepsy are devastating conditions mandating an accurate diagnosis to guide proper management. Whole-exome sequencing was used to investigate the disease etiology in four children from independent families with intellectual disability and epilepsy, revealing bi-allelic GOT2 mutations. In-depth metabolic studies in individual 1 showed low plasma serine, hypercitrullinemia, hyperlactatemia, and hyperammonemia. The epilepsy was serine and pyridoxine responsive. Functional consequences of observed mutations were tested by measuring enzyme activity and by cell and animal models. Zebrafish and mouse models were used to validate brain developmental and functional defects and to test therapeutic strategies. GOT2 encodes the mitochondrial glutamate oxaloacetate transaminase. GOT2 enzyme activity was deficient in fibroblasts with bi-allelic mutations. GOT2, a member of the malate-aspartate shuttle, plays an essential role in the intracellular NAD(H) redox balance. De novo serine biosynthesis was impaired in fibroblasts with GOT2 mutations and GOT2-knockout HEK293 cells. Correcting the highly oxidized cytosolic NAD-redox state by pyruvate~supplementation restored serine biosynthesis in GOT2-deficient cells. Knockdown of got2a in zebrafish resulted in a brain developmental defect associated with seizure-like electroencephalography spikes, which could be rescued by supplying pyridoxine in embryo water. Both pyridoxine and serine synergistically rescued embryonic developmental defects in zebrafish got2a morphants. The two treated individuals reacted favorably to their treatment. Our data provide a mechanistic basis for the biochemical abnormalities in GOT2 deficiency that may also hold for other MAS defects.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.07.015}, author = {van Karnebeek, Clara D M and Ramos, R{\'u}ben J and Wen, Xiao-Yan and Tarailo-Graovac, Maja and Gleeson, Joseph G and Skrypnyk, Cristina and Brand-Arzamendi, Koroboshka and Karbassi, Farhad and Issa, Mahmoud Y and van der Lee, Robin and Dr{\"o}gem{\"o}ller, Britt I and Koster, Janet and Rousseau, Justine and Campeau, Philippe M and Wang, Youdong and Cao, Feng and Li, Meng and Ruiter, Jos and Ciapaite, Jolita and Kluijtmans, Leo A J and Willemsen, Michel A A P and Jans, Judith J and Ross, Colin J and Wintjes, Liesbeth T and Rodenburg, Richard J and Huigen, Marleen C D G and Jia, Zhengping and Waterham, Hans R and Wasserman, Wyeth W and Wanders, Ronald J A and Verhoeven-Duif, Nanda M and Zaki, Maha S and Wevers, Ron A} } @article {81, title = {Drug-Resistant Juvenile Myoclonic Epilepsy: Misdiagnosis of Progressive Myoclonus Epilepsy.}, journal = {Front Neurol}, volume = {10}, year = {2019}, month = {2019}, pages = {946}, abstract = {

Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome characterized by bilateral myoclonic and tonic-clonic seizures typically starting in adolescence and responding well to medication. Misdiagnosis of a more severe progressive myoclonus epilepsy (PME) as JME has been suggested as a cause of drug-resistance. Medical records of the Epilepsy Center Hessen-Marburg between 2005 and 2014 were automatically selected using keywords and manually reviewed regarding the presence of a JME diagnosis at any timepoint. The identified patients were evaluated regarding seizure outcome and drug resistance according to ILAE criteria. 87/168 identified JME patients were seizure-free at last follow-up including 61 drug-responsive patients (group NDR). Seventy-eight patients were not seizure-free including 26 drug-resistant patients (group DR). Valproate was the most efficacious AED. The JME diagnosis was revised in 7 patients of group DR including 6 in whom the diagnosis had already been questioned or revised during clinical follow-up. One of these was finally diagnosed with PME (genetically confirmed Lafora disease) based on genetic testing. She was initially reviewed at age 29 yrs and considered to be inconsistent with PME. Intellectual disability ( = 0.025), cognitive impairment ( < 0.001), febrile seizures in first-degree relatives ( = 0.023) and prominent dialeptic seizures ( = 0.009) where significantly more frequent in group DR. Individuals with PME are rarely found among drug-resistant alleged JME patients in a tertiary epilepsy center. Even a very detailed review by experienced epileptologists may not identify the presence of PME before the typical features evolve underpinning the need for early genetic testing in drug-resistant JME patients.

}, issn = {1664-2295}, doi = {10.3389/fneur.2019.00946}, author = {Martin, Sarah and Strzelczyk, Adam and Lindlar, Silvia and Krause, Kristina and Reif, Philipp S and Menzler, Katja and Chiocchetti, Andreas G and Rosenow, Felix and Knake, Susanne and Klein, Karl Martin} } @article {58, title = {EphrinB2-EphB4-RASA1 Signaling in Human Cerebrovascular Development and Disease.}, journal = {Trends Mol Med}, volume = {25}, year = {2019}, month = {2019 Apr}, pages = {265-286}, abstract = {

Recent whole exome sequencing studies in humans have provided novel insight into the importance of the ephrinB2-EphB4-RASA1 signaling axis in cerebrovascular development, corroborating and extending previous work in model systems. Here, we aim to review the human cerebrovascular phenotypes associated with ephrinB2-EphB4-RASA1 mutations, including those recently discovered in Vein of Galen malformation: the most common and severe brain arteriovenous malformation in neonates. We will also discuss emerging paradigms of the molecular and cellular pathophysiology of disease-causing ephrinB2-EphB4-RASA1 mutations, including the potential role of somatic mosaicism. These observations have potential diagnostic and therapeutic implications for patients with rare congenital cerebrovascular diseases and their families.

}, issn = {1471-499X}, doi = {10.1016/j.molmed.2019.01.009}, author = {Zeng, Xue and Hunt, Ava and Jin, Sheng Chih and Duran, Daniel and Gaillard, Jonathan and Kahle, Kristopher T} } @article {61, title = {Genetic architecture of laterality defects revealed by whole exome sequencing.}, journal = {Eur J Hum Genet}, volume = {27}, year = {2019}, month = {2019 Apr}, pages = {563-573}, abstract = {

Aberrant left-right patterning in the developing human embryo can lead to a broad spectrum of congenital malformations. The causes of most laterality defects are not known, with variants in established genes accounting for <20\% of cases. We sought to characterize the genetic spectrum of these conditions by performing whole-exome sequencing of 323 unrelated laterality cases. We investigated the role of rare, predicted-damaging variation in 1726 putative laterality candidate genes derived from model organisms, pathway analyses, and human phenotypes. We also evaluated the contribution of homo/hemizygous exon deletions and gene-based burden of rare variation. A total of 28 candidate variants (26 rare predicted-damaging variants and 2 hemizygous deletions) were identified, including variants in genes known to cause heterotaxy and primary ciliary dyskinesia (ACVR2B, NODAL, ZIC3, DNAI1, DNAH5, HYDIN, MMP21), and genes without a human phenotype association, but with prior evidence for a role in embryonic laterality or cardiac development. Sanger validation of the latter variants in probands and their parents revealed no de novo variants, but apparent transmitted heterozygous (ROCK2, ISL1, SMAD2), and hemizygous (RAI2, RIPPLY1) variant patterns. Collectively, these variants account for 7.1\% of our study subjects. We also observe evidence for an excess burden of rare, predicted loss-of-function variation in PXDNL and BMS1- two genes relevant to the broader laterality phenotype. These findings highlight potential new genes in the development of laterality defects, and suggest extensive locus heterogeneity and complex genetic models in this class of birth defects.

}, issn = {1476-5438}, doi = {10.1038/s41431-018-0307-z}, author = {Li, Alexander H and Hanchard, Neil A and Azamian, Mahshid and D{\textquoteright}Alessandro, Lisa C A and Coban-Akdemir, Zeynep and Lopez, Keila N and Hall, Nancy J and Dickerson, Heather and Nicosia, Annarita and Fernbach, Susan and Boone, Philip M and Gambin, Tomaz and Karaca, Ender and Gu, Shen and Yuan, Bo and Jhangiani, Shalini N and Doddapaneni, HarshaVardhan and Hu, Jianhong and Dinh, Huyen and Jayaseelan, Joy and Muzny, Donna and Lalani, Seema and Towbin, Jeffrey and Penny, Daniel and Fraser, Charles and Martin, James and Lupski, James R and Gibbs, Richard A and Boerwinkle, Eric and Ware, Stephanie M and Belmont, John W} } @article {60, title = {Insights into genetics, human biology and disease gleaned from family based genomic studies.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 04}, pages = {798-812}, abstract = {

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75\% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in~novel "disease gene" discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

}, issn = {1530-0366}, doi = {10.1038/s41436-018-0408-7}, author = {Posey, Jennifer E and O{\textquoteright}Donnell-Luria, Anne H and Chong, Jessica X and Harel, Tamar and Jhangiani, Shalini N and Coban Akdemir, Zeynep H and Buyske, Steven and Pehlivan, Davut and Carvalho, Claudia M B and Baxter, Samantha and Sobreira, Nara and Liu, Pengfei and Wu, Nan and Rosenfeld, Jill A and Kumar, Sushant and Avramopoulos, Dimitri and White, Janson J and Doheny, Kimberly F and Witmer, P Dane and Boehm, Corinne and Sutton, V Reid and Muzny, Donna M and Boerwinkle, Eric and G{\"u}nel, Murat and Nickerson, Deborah A and Mane, Shrikant and MacArthur, Daniel G and Gibbs, Richard A and Hamosh, Ada and Lifton, Richard P and Matise, Tara C and Rehm, Heidi L and Gerstein, Mark and Bamshad, Michael J and Valle, David and Lupski, James R} } @article {59, title = {Monogenic causes of chronic kidney disease in adults.}, journal = {Kidney Int}, volume = {95}, year = {2019}, month = {2019 Apr}, pages = {914-928}, abstract = {

Approximately 500 monogenic causes of chronic kidney disease (CKD) have been identified, mainly in pediatric populations. The frequency of monogenic causes among adults with CKD has been less extensively studied. To determine the likelihood of detecting monogenic causes of CKD in adults presenting to nephrology services in Ireland, we conducted whole exome sequencing (WES) in a multi-centre cohort of 114 families including 138 affected individuals with CKD. Affected adults were recruited from 78 families with a positive family history, 16 families with extra-renal features, and 20 families with neither a family history nor extra-renal features. We detected a pathogenic mutation in a known CKD gene in 42 of 114 families (37\%). A monogenic cause was identified in 36\% of affected families with a positive family history of CKD, 69\% of those with extra-renal features, and only 15\% of those without a family history or extra-renal features. There was no difference in the rate of genetic diagnosis in individuals with childhood versus adult onset CKD. Among the 42 families in whom a monogenic cause was identified, WES confirmed the clinical diagnosis in 17 (40\%), corrected the clinical diagnosis in 9 (22\%), and established a diagnosis for the first time in 16 families referred with CKD of unknown etiology (38\%). In this multi-centre study of adults with CKD, a molecular genetic diagnosis was established in over one-third of families. In the evolving era of precision medicine, WES may be an important tool to identify the cause of CKD in adults.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2018.10.031}, author = {Connaughton, Dervla M and Kennedy, Claire and Shril, Shirlee and Mann, Nina and Murray, Susan L and Williams, Patrick A and Conlon, Eoin and Nakayama, Makiko and van der Ven, Amelie T and Ityel, Hadas and Kause, Franziska and Kolvenbach, Caroline M and Dai, Rufeng and Vivante, Asaf and Braun, Daniela A and Schneider, Ronen and Kitzler, Thomas M and Moloney, Brona and Moran, Conor P and Smyth, John S and Kennedy, Alan and Benson, Katherine and Stapleton, Caragh and Denton, Mark and Magee, Colm and O{\textquoteright}Seaghdha, Conall M and Plant, William D and Griffin, Matthew D and Awan, Atif and Sweeney, Clodagh and Mane, Shrikant M and Lifton, Richard P and Griffin, Brenda and Leavey, Sean and Casserly, Liam and de Freitas, Declan G and Holian, John and Dorman, Anthony and Doyle, Brendan and Lavin, Peter J and Little, Mark A and Conlon, Peter J and Hildebrandt, Friedhelm} } @article {71, title = {MSTO1 mutations cause mtDNA depletion, manifesting as muscular dystrophy with cerebellar involvement.}, journal = {Acta Neuropathol}, year = {2019}, month = {2019 Aug 29}, abstract = {

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype-phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70\% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.

}, issn = {1432-0533}, doi = {10.1007/s00401-019-02059-z}, author = {Donkervoort, S and Sabouny, R and Yun, P and Gauquelin, L and Chao, K R and Hu, Y and Al Khatib, I and T{\"o}pf, A and Mohassel, P and Cummings, B B and Kaur, R and Saade, D and Moore, S A and Waddell, L B and Farrar, M A and Goodrich, J K and Uapinyoying, P and Chan, S H S and Javed, A and Leach, M E and Karachunski, P and Dalton, J and Medne, L and Harper, A and Thompson, C and Thiffault, I and Specht, S and Lamont, R E and Saunders, C and Racher, H and Bernier, F P and Mowat, D and Witting, N and Vissing, J and Hanson, R and Coffman, K A and Hainlen, M and Parboosingh, J S and Carnevale, A and Yoon, G and Schnur, R E and Boycott, K M and Mah, J K and Straub, V and Foley, A Reghan and Innes, A M and B{\"o}nnemann, C G and Shutt, T E} } @article {74, title = {Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.}, journal = {Am J Med Genet A}, volume = {179}, year = {2019}, month = {2019 Oct}, pages = {2112-2118}, abstract = {

Generalized arterial calcifications of infancy (GACI) is caused by mutations in ENPP1. Other ENPP1-related phenotypes include pseudoxanthoma elasticum, hypophosphatemic rickets, and Cole disease. We studied four children from two Bedouin consanguineous families who presented with severe clinical phenotype including thrombocytopenia, hypoglycemia, hepatic, and neurologic manifestations. Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. Whole exome sequencing (WES) was performed for affected children and their parents. Following the identification of a novel mutation in the ENPP1 gene, we characterized this novel multisystemic presentation and revised relevant imaging studies. Using WES, we identified a novel homozygous mutation (c.556G > C; p.Gly186Arg) in ENPP1 which affects a highly conserved protein domain (somatomedin B2). ENPP1-associated genetic diseases exhibit phenotypic heterogeneity depending on mutation type and location. Follow-up clinical characterization of these families allowed us to revise and detect new features of systemic calcifications, which established the diagnosis of GACI, expanding the phenotypic spectrum associated with ENPP1 mutations. Our findings demonstrate that this novel ENPP1 founder mutation can cause a fatal multisystemic phenotype, mimicking severe congenital infection. This also represents the first reported mutation affecting the SMB2 domain, associated with GACI.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61334}, author = {Staretz-Chacham, Orna and Shukrun, Rachel and Barel, Ortal and Pode-Shakked, Ben and Pleniceanu, Oren and Anikster, Yair and Shalva, Nechama and Ferreira, Carlos R and Ben-Haim Kadosh, Admit and Richardson, Justin and Mane, Shrikant M and Hildebrandt, Friedhelm and Vivante, Asaf} } @article {57, title = {Novel parent-of-origin-specific differentially methylated loci on chromosome 16.}, journal = {Clin Epigenetics}, volume = {11}, year = {2019}, month = {2019 Apr 08}, pages = {60}, abstract = {

BACKGROUND: Congenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise almost exclusively on the maternally inherited chromosome 16. Given the phenotypic similarities between upd(16)mat and ACDMPV, together with parental allelic bias in ACDMPV, we hypothesized that there may be unknown imprinted loci mapping to chromosome 16 that become functionally unmasked by chromosomal structural variants.

RESULTS: To identify parent-of-origin biased DNA methylation, we performed high-resolution bisulfite sequencing of chromosome 16 on peripheral blood and cultured skin fibroblasts from individuals with maternal or paternal upd(16) as well as lung tissue from patients with ACDMPV-causative 16q24.1 deletions and a normal control. We identified 22 differentially methylated regions (DMRs) with >= 5 consecutive CpG methylation sites and varying tissue-specificity, including the known DMRs associated with the established imprinted gene ZNF597 and DMRs supporting maternal methylation of PRR25, thought to be paternally expressed in lymphoblastoid cells. Lastly, we found evidence of paternal methylation on 16q24.1 near LINC01082 mapping to the FOXF1 enhancer.

CONCLUSIONS: Using high-resolution bisulfite sequencing to evaluate DNA methylation across chromosome 16, we found evidence for novel candidate imprinted loci on chromosome 16 that would not be evident in array-based assays and could contribute to the birth defects observed in patients with upd(16)mat or in ACDMPV.

}, issn = {1868-7083}, doi = {10.1186/s13148-019-0655-8}, author = {Schulze, Katharina V and Szafranski, Przemyslaw and Lesmana, Harry and Hopkin, Robert J and Hamvas, Aaron and Wambach, Jennifer A and Shinawi, Marwan and Zapata, Gladys and Carvalho, Claudia M B and Liu, Qian and Karolak, Justyna A and Lupski, James R and Hanchard, Neil A and Stankiewicz, Pawe{\l}} } @article {69, title = {The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy.}, journal = {Genet Med}, year = {2019}, month = {2019 Sep 02}, abstract = {

PURPOSE: Moyamoya angiopathy (MMA) is a cerebrovascular disease characterized by occlusion of large arteries, which leads to strokes starting in childhood. Twelve altered genes predispose to MMA but the majority of cases of European descent do not have an identified genetic trigger.

METHODS: Exome sequencing from 39 trios were analyzed.

RESULTS: We identified four de novo variants in three genes not previously associated with MMA: CHD4, CNOT3, and SETD5. Identification of additional rare variants in these genes in 158 unrelated MMA probands provided further support that rare pathogenic variants in CHD4 and CNOT3 predispose to MMA. Previous studies identified de novo variants in these genes in children with developmental disorders (DD), intellectual disability, and congenital heart disease.

CONCLUSION: These genes encode proteins involved in chromatin remodeling, and taken together with previously reported genes leading to MMA-like cerebrovascular occlusive disease (YY1AP1, SMARCAL1), implicate disrupted chromatin remodeling as a molecular pathway predisposing to early onset, large artery occlusive cerebrovascular disease. Furthermore, these data expand the spectrum of phenotypic pleiotropy due to alterations of CHD4, CNOT3, and SETD5 beyond DD to later onset disease in the cerebrovascular arteries and emphasize the need to assess clinical complications into adulthood for genes associated with DD.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0639-2}, author = {Pinard, Am{\'e}lie and Guey, St{\'e}phanie and Guo, Dongchuan and Cecchi, Alana C and Kharas, Natasha and Wallace, Stephanie and Regalado, Ellen S and Hostetler, Ellen M and Sharrief, Anjail Z and Bergametti, Fran{\c c}oise and Kossorotoff, Manoelle and Herv{\'e}, Dominique and Kraemer, Markus and Bamshad, Michael J and Nickerson, Deborah A and Smith, Edward R and Tournier-Lasserve, Elisabeth and Milewicz, Dianna M} } @article {70, title = {Redefining the Etiologic Landscape of Cerebellar Malformations.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Sep 05}, pages = {606-615}, abstract = {

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51\%) than for DWM (16\%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19\%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85\%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47\%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.07.019}, author = {Aldinger, Kimberly A and Timms, Andrew E and Thomson, Zachary and Mirzaa, Ghayda M and Bennett, James T and Rosenberg, Alexander B and Roco, Charles M and Hirano, Matthew and Abidi, Fatima and Haldipur, Parthiv and Cheng, Chi V and Collins, Sarah and Park, Kaylee and Zeiger, Jordan and Overmann, Lynne M and Alkuraya, Fowzan S and Biesecker, Leslie G and Braddock, Stephen R and Cathey, Sara and Cho, Megan T and Chung, Brian H Y and Everman, David B and Zarate, Yuri A and Jones, Julie R and Schwartz, Charles E and Goldstein, Amy and Hopkin, Robert J and Krantz, Ian D and Ladda, Roger L and Leppig, Kathleen A and McGillivray, Barbara C and Sell, Susan and Wusik, Katherine and Gleeson, Joseph G and Nickerson, Deborah A and Bamshad, Michael J and Gerrelli, Dianne and Lisgo, Steven N and Seelig, Georg and Ishak, Gisele E and Barkovich, A James and Curry, Cynthia J and Glass, Ian A and Millen, Kathleen J and Doherty, Dan and Dobyns, William B} } @article {50, title = {Whole-Genome Sequencing to Characterize Monogenic and Polygenic Contributions in Patients Hospitalized With Early-Onset Myocardial Infarction.}, journal = {Circulation}, volume = {139}, year = {2019}, month = {2019 Mar 26}, pages = {1593-1602}, abstract = {

BACKGROUND: The relative prevalence and clinical importance of monogenic mutations related to familial hypercholesterolemia and of high polygenic score (cumulative impact of many common variants) pathways for early-onset myocardial infarction remain uncertain. Whole-genome sequencing enables simultaneous ascertainment of both monogenic mutations and polygenic score for each individual.

METHODS: We performed deep-coverage whole-genome sequencing of 2081 patients from 4 racial subgroups hospitalized in the United States with early-onset myocardial infarction (age <=55 years) recruited with a 2:1 female-to-male enrollment design. We compared these genomes with those of 3761 population-based control subjects. We first identified individuals with a rare, monogenic mutation related to familial hypercholesterolemia. Second, we calculated a recently developed polygenic score of 6.6 million common DNA variants to quantify the cumulative susceptibility conferred by common variants. We defined high polygenic score as the top 5\% of the control distribution because this cutoff has previously been shown to confer similar risk to that of familial hypercholesterolemia mutations.

RESULTS: The mean age of the 2081 patients presenting with early-onset myocardial infarction was 48 years, and 66\% were female. A familial hypercholesterolemia mutation was present in 36 of these patients (1.7\%) and was associated with a 3.8-fold (95\% CI, 2.1-6.8; P<0.001) increased odds of myocardial infarction. Of the patients with early-onset myocardial infarction, 359 (17.3\%) carried a high polygenic score, associated with a 3.7-fold (95\% CI, 3.1-4.6; P<0.001) increased odds. Mean estimated untreated low-density lipoprotein cholesterol was 206 mg/dL in those with a familial hypercholesterolemia mutation, 132 mg/dL in those with high polygenic score, and 122 mg/dL in those in the remainder of the population. Although associated with increased risk in all racial groups, high polygenic score demonstrated the strongest association in white participants ( P for heterogeneity=0.008).

CONCLUSIONS: Both familial hypercholesterolemia mutations and high polygenic score are associated with a >3-fold increased odds of early-onset myocardial infarction. However, high polygenic score has a 10-fold higher prevalence among patients presents with early-onset myocardial infarction.

CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00597922.

}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.118.035658}, author = {Khera, Amit V and Chaffin, Mark and Zekavat, Seyedeh M and Collins, Ryan L and Roselli, Carolina and Natarajan, Pradeep and Lichtman, Judith H and D{\textquoteright}Onofrio, Gail and Mattera, Jennifer and Dreyer, Rachel and Spertus, John A and Taylor, Kent D and Psaty, Bruce M and Rich, Stephen S and Post, Wendy and Gupta, Namrata and Gabriel, Stacey and Lander, Eric and Ida Chen, Yii-Der and Talkowski, Michael E and Rotter, Jerome I and Krumholz, Harlan M and Kathiresan, Sekar} } @article {38, title = {Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 Apr 24}, pages = {1613}, abstract = {

Less than 3\% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5\%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

}, keywords = {Databases, Genetic, Diabetes Mellitus, Type 2, Disease, Gene Frequency, Genetic Testing, Genetic Variation, Humans, Obesity, Phenotype, Proteins, Respiratory Hypersensitivity, United Kingdom}, issn = {2041-1723}, doi = {10.1038/s41467-018-03911-8}, author = {Emdin, Connor A and Khera, Amit V and Chaffin, Mark and Klarin, Derek and Natarajan, Pradeep and Aragam, Krishna and Haas, Mary and Bick, Alexander and Zekavat, Seyedeh M and Nomura, Akihiro and Ardissino, Diego and Wilson, James G and Schunkert, Heribert and McPherson, Ruth and Watkins, Hugh and Elosua, Roberto and Bown, Matthew J and Samani, Nilesh J and Baber, Usman and Erdmann, Jeanette and Gupta, Namrata and Danesh, John and Chasman, Daniel and Ridker, Paul and Denny, Joshua and Bastarache, Lisa and Lichtman, Judith H and D{\textquoteright}Onofrio, Gail and Mattera, Jennifer and Spertus, John A and Sheu, Wayne H-H and Taylor, Kent D and Psaty, Bruce M and Rich, Stephen S and Post, Wendy and Rotter, Jerome I and Chen, Yii-Der Ida and Krumholz, Harlan and Saleheen, Danish and Gabriel, Stacey and Kathiresan, Sekar} } @article {44, title = {Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage.}, journal = {Stroke}, volume = {49}, year = {2018}, month = {2018 Nov}, pages = {2652-2658}, abstract = {

Background and Purpose- Whether to resume oral anticoagulation treatment after intracerebral hemorrhage (ICH) remains an unresolved question. Previous studies focused primarily on recurrent stroke after ICH. We sought to investigate the association between cardioembolic stroke risk, oral anticoagulation therapy resumption, and functional recovery among ICH survivors in the absence of recurrent stroke. Methods- We conducted a joint analysis of 3 observational studies: (1) the multicenter RETRACE study (German-Wide Multicenter Analysis of Oral Anticoagulation Associated Intracerebral Hemorrhage); (2) the Massachusetts General Hospital ICH study (n=166); and (3) the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage; n=131). We included 941 survivors of ICH in the setting of active oral anticoagulation therapy for prevention of cardioembolic stroke because of nonvalvular atrial fibrillation and without evidence of ischemic stroke and recurrent ICH at 1 year from the index event. We created univariable and multivariable models to explore associations between cardioembolic stroke risk (based on CHADS-VASc scores) and functional recovery after ICH, defined as achieving modified Rankin Scale score of <=3 at 1 year for participants with modified Rankin Scale score of >3 at discharge. Results- In multivariable analyses, the CHADS-VASc score was associated with a decreased likelihood of functional recovery (odds ratio, 0.83 per 1 point increase; 95\% CI, 0.79-0.86) at 1 year. Anticoagulation resumption was independently associated with a higher likelihood of recovery, regardless of CHADS-VASc score (odds ratio, 1.89; 95\% CI, 1.32-2.70). We found an interaction between CHADS-VASc score and anticoagulation resumption in terms of association with increased likelihood of functional recovery (interaction P=0.011). Conclusions- Increasing cardioembolic stroke risk is associated with a decreased likelihood of functional recovery at 1 year after ICH, but this association was weaker among participants resuming oral anticoagulation therapy. These findings support, including recovery metrics, in future studies of anticoagulation resumption after ICH.

}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.118.021799}, author = {Murphy, Meredith P and Kuramatsu, Joji B and Leasure, Audrey and Falcone, Guido J and Kamel, Hooman and Sansing, Lauren H and Kourkoulis, Christina and Schwab, Kristin and Elm, Jordan J and Gurol, M Edip and Tran, Huy and Greenberg, Steven M and Viswanathan, Anand and Anderson, Christopher D and Schwab, Stefan and Rosand, Jonathan and Shi, Fu-Dong and Kittner, Steven J and Testai, Fernando D and Woo, Daniel and Langefeld, Carl D and James, Michael L and Koch, Sebastian and Huttner, Hagen B and Biffi, Alessandro and Sheth, Kevin N} } @article {40, title = {Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line.}, journal = {Genome Res}, volume = {28}, year = {2018}, month = {2018 08}, pages = {1126-1135}, abstract = {

The SK-BR-3 cell line is one of the most important models for HER2+ breast cancers, which affect one in five breast cancer patients. SK-BR-3 is known to be highly rearranged, although much of the variation is in complex and repetitive regions that may be underreported. Addressing this, we sequenced SK-BR-3 using long-read single molecule sequencing from Pacific Biosciences and develop one of the most detailed maps of structural variations (SVs) in a cancer genome available, with nearly 20,000 variants present, most of which were missed by short-read sequencing. Surrounding the important oncogene (also known as ), we discover a complex sequence of nested duplications and translocations, suggesting a punctuated progression. Full-length transcriptome sequencing further revealed several novel gene fusions within the nested genomic variants. Combining long-read genome and transcriptome sequencing enables an in-depth analysis of how SVs disrupt the genome and sheds new light on the complex mechanisms involved in cancer genome evolution.

}, keywords = {Breast Neoplasms, Female, Gene Amplification, Gene Rearrangement, Genome, Human, Genomic Structural Variation, High-Throughput Nucleotide Sequencing, Humans, MCF-7 Cells, Oncogenes, Receptor, ErbB-2, Repetitive Sequences, Nucleic Acid, Transcriptome}, issn = {1549-5469}, doi = {10.1101/gr.231100.117}, author = {Nattestad, Maria and Goodwin, Sara and Ng, Karen and Baslan, Timour and Sedlazeck, Fritz J and Rescheneder, Philipp and Garvin, Tyler and Fang, Han and Gurtowski, James and Hutton, Elizabeth and Tseng, Elizabeth and Chin, Chen-Shan and Beck, Timothy and Sundaravadanam, Yogi and Kramer, Melissa and Antoniou, Eric and McPherson, John D and Hicks, James and McCombie, W Richard and Schatz, Michael C} } @article {45, title = {Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 10 02}, pages = {4038}, abstract = {

Hundreds of thousands of human whole genome sequencing (WGS) datasets will be generated over the next few years. These data are more valuable in aggregate: joint analysis of genomes from many sources increases sample size and statistical power. A central challenge for joint analysis is that different WGS data processing pipelines cause substantial differences in variant calling in combined datasets, necessitating computationally expensive reprocessing. This approach is no longer tenable given the scale of current studies and data volumes. Here, we define WGS data processing standards that allow different groups to produce functionally equivalent (FE) results, yet still innovate on data processing pipelines. We present initial FE pipelines developed at five genome centers and show that they yield similar variant calling results and produce significantly less variability than sequencing replicates. This work alleviates a key technical bottleneck for genome aggregation and helps lay the foundation for community-wide human genetics studies.

}, keywords = {Genome, Human, Human Genetics, Humans, Whole Genome Sequencing}, issn = {2041-1723}, doi = {10.1038/s41467-018-06159-4}, author = {Regier, Allison A and Farjoun, Yossi and Larson, David E and Krasheninina, Olga and Kang, Hyun Min and Howrigan, Daniel P and Chen, Bo-Juen and Kher, Manisha and Banks, Eric and Ames, Darren C and English, Adam C and Li, Heng and Xing, Jinchuan and Zhang, Yeting and Matise, Tara and Abecasis, Goncalo R and Salerno, Will and Zody, Michael C and Neale, Benjamin M and Hall, Ira M} } @article {43, title = {Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1219-1224}, abstract = {

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5\% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0183-z}, author = {Khera, Amit V and Chaffin, Mark and Aragam, Krishna G and Haas, Mary E and Roselli, Carolina and Choi, Seung Hoan and Natarajan, Pradeep and Lander, Eric S and Lubitz, Steven A and Ellinor, Patrick T and Kathiresan, Sekar} } @article {48, title = {The phenotypic spectrum of Xia-Gibbs syndrome.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 06}, pages = {1315-1326}, abstract = {

Xia-Gibbs syndrome (XGS: OMIM $\#$ 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines.

}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38699}, author = {Jiang, Yunyun and Wangler, Michael F and McGuire, Amy L and Lupski, James R and Posey, Jennifer E and Khayat, Michael M and Murdock, David R and Sanchez-Pulido, Luis and Ponting, Chris P and Xia, Fan and Hunter, Jill V and Meng, Qingchang and Murugan, Mullai and Gibbs, Richard A} } @article {42, title = {Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.}, journal = {Am J Respir Crit Care Med}, volume = {197}, year = {2018}, month = {2018 Jun 15}, pages = {1552-1564}, abstract = {

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.

OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.

METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.

MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 {\texttimes} 10) and suggestive (P < 7.06 {\texttimes} 10) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.

CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

}, issn = {1535-4970}, doi = {10.1164/rccm.201712-2529OC}, author = {Mak, Angel C Y and White, Marquitta J and Eckalbar, Walter L and Szpiech, Zachary A and Oh, Sam S and Pino-Yanes, Maria and Hu, Donglei and Goddard, Pag{\'e} and Huntsman, Scott and Galanter, Joshua and Wu, Ann Chen and Himes, Blanca E and Germer, Soren and Vogel, Julia M and Bunting, Karen L and Eng, Celeste and Salazar, Sandra and Keys, Kevin L and Liberto, Jennifer and Nuckton, Thomas J and Nguyen, Thomas A and Torgerson, Dara G and Kwok, Pui-Yan and Levin, Albert M and Celed{\'o}n, Juan C and Forno, Erick and Hakonarson, Hakon and Sleiman, Patrick M and Dahlin, Amber and Tantisira, Kelan G and Weiss, Scott T and Serebrisky, Denise and Brigino-Buenaventura, Emerita and Farber, Harold J and Meade, Kelley and Lenoir, Michael A and Avila, Pedro C and Sen, Saunak and Thyne, Shannon M and Rodriguez-Cintron, William and Winkler, Cheryl A and Moreno-Estrada, Andr{\'e}s and Sandoval, Karla and Rodriguez-Santana, Jose R and Kumar, Rajesh and Williams, L Keoki and Ahituv, Nadav and Ziv, Elad and Seibold, Max A and Darnell, Robert B and Zaitlen, Noah and Hernandez, Ryan D and Burchard, Esteban G} } @article {12, title = {ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.}, journal = {J Am Coll Cardiol}, volume = {69}, year = {2017}, month = {2017 Apr 25}, pages = {2054-2063}, abstract = {

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3~major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3~wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were~defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in~<25\% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17\% reduction in circulating triglycerides and a 12\% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34\% reduction in odds of CAD (odds ratio: 0.66; 95\% confidence interval: 0.44 to 0.98; p~= 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95\% confidence interval: 0.55 to 0.77; p~< 0.001).

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

}, keywords = {Adult, Angiopoietin-Like Protein 3, Angiopoietin-like Proteins, Angiopoietins, Animals, Atherosclerosis, Case-Control Studies, Coronary Artery Disease, Female, Humans, Lipids, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Missense, Myocardial Infarction, Risk Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2017.02.030}, author = {Stitziel, Nathan O and Khera, Amit V and Wang, Xiao and Bierhals, Andrew J and Vourakis, A Christina and Sperry, Alexandra E and Natarajan, Pradeep and Klarin, Derek and Emdin, Connor A and Zekavat, Seyedeh M and Nomura, Akihiro and Erdmann, Jeanette and Schunkert, Heribert and Samani, Nilesh J and Kraus, William E and Shah, Svati H and Yu, Bing and Boerwinkle, Eric and Rader, Daniel J and Gupta, Namrata and Frossard, Philippe M and Rasheed, Asif and Danesh, John and Lander, Eric S and Gabriel, Stacey and Saleheen, Danish and Musunuru, Kiran and Kathiresan, Sekar} } @article {17, title = {Is Coronary Atherosclerosis One Disease or Many? Setting Realistic Expectations for Precision Medicine.}, journal = {Circulation}, volume = {135}, year = {2017}, month = {2017 Mar 14}, pages = {1005-1007}, keywords = {Atherosclerosis, Coronary Artery Disease, Humans, Precision Medicine}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.116.026479}, author = {Khera, Amit V and Kathiresan, Sekar} } @article {14, title = {Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 Apr}, pages = {527-536}, abstract = {

Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

}, keywords = {Animals, Ataxin-1, Autism Spectrum Disorder, Cerebellum, Female, Humans, Intellectual Disability, Interpersonal Relations, Male, Mice, Nerve Tissue Proteins, Neurodegenerative Diseases, Nuclear Proteins, Phenotype, Repressor Proteins}, issn = {1546-1718}, doi = {10.1038/ng.3808}, author = {Lu, Hsiang-Chih and Tan, Qiumin and Rousseaux, Maxime W C and Wang, Wei and Kim, Ji-Yoen and Richman, Ronald and Wan, Ying-Wooi and Yeh, Szu-Ying and Patel, Jay M and Liu, Xiuyun and Lin, Tao and Lee, Yoontae and Fryer, John D and Han, Jing and Chahrour, Maria and Finnell, Richard H and Lei, Yunping and Zurita-Jimenez, Maria E and Ahimaz, Priyanka and Anyane-Yeboa, Kwame and Van Maldergem, Lionel and Lehalle, Daphne and Jean-Marcais, Nolwenn and Mosca-Boidron, Anne-Laure and Thevenon, Julien and Cousin, Margot A and Bro, Della E and Lanpher, Brendan C and Klee, Eric W and Alexander, Nora and Bainbridge, Matthew N and Orr, Harry T and Sillitoe, Roy V and Ljungberg, M Cecilia and Liu, Zhandong and Schaaf, Christian P and Zoghbi, Huda Y} } @article {28, title = {Exome sequencing reveals novel genetic loci influencing obesity-related traits in Hispanic children.}, journal = {Obesity (Silver Spring)}, volume = {25}, year = {2017}, month = {2017 Jul}, pages = {1270-1276}, abstract = {

OBJECTIVE: To perform whole exome sequencing in 928 Hispanic children and identify variants and genes associated with childhood obesity.

METHODS: Single-nucleotide variants (SNVs) were identified from Illumina whole exome sequencing data using integrated read mapping, variant calling, and an annotation pipeline (Mercury). Association analyses of 74 obesity-related traits and exonic variants were performed using SeqMeta software. Rare autosomal variants were analyzed using gene-based association analyses, and common autosomal variants were analyzed at the SNV level.

RESULTS: (1) Rare exonic variants in 10 genes and 16 common SNVs in 11 genes that were associated with obesity traits in a cohort of Hispanic children were identified, (2) novel rare variants in peroxisome biogenesis factor 1 (PEX1) associated with several obesity traits (weight, weight z score, BMI, BMI z score, waist circumference, fat mass, trunk fat mass) were discovered, and (3) previously reported SNVs associated with childhood obesity were replicated.

CONCLUSIONS: Convergence of whole exome sequencing, a family-based design, and extensive phenotyping discovered novel rare and common variants associated with childhood obesity. Linking PEX1 to obesity phenotypes poses a novel mechanism of peroxisomal biogenesis and metabolism underlying the development of childhood obesity.

}, keywords = {Adolescent, ATPases Associated with Diverse Cellular Activities, Body Mass Index, Body Weight, Child, Child, Preschool, Cohort Studies, Exome, Genetic Loci, Genome-Wide Association Study, Hispanic or Latino, Humans, Membrane Proteins, Pediatric Obesity, Polymorphism, Single Nucleotide, Risk Factors, Sequence Analysis, DNA, Software, Waist Circumference, Young Adult}, issn = {1930-739X}, doi = {10.1002/oby.21869}, author = {Sabo, Aniko and Mishra, Pamela and Dugan-Perez, Shannon and Voruganti, V Saroja and Kent, Jack W and Kalra, Divya and Cole, Shelley A and Comuzzie, Anthony G and Muzny, Donna M and Gibbs, Richard A and Butte, Nancy F} } @article {25, title = {Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations.}, journal = {Nat Commun}, volume = {8}, year = {2017}, month = {2017 Aug 16}, pages = {266}, abstract = {

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5{\textquoteright}-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease.Insight into the genetic influence on the immune response is important for the understanding of interindividual variability in human pathologies. Here, the authors generate transcriptome data from human blood monocytes stimulated with various immune stimuli and provide a time-resolved response eQTL map.

}, keywords = {Acetylmuramyl-Alanyl-Isoglutamine, Adjuvants, Immunologic, Adolescent, Adult, Autoimmune Diseases, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Genetic Predisposition to Disease, Healthy Volunteers, Humans, Indicators and Reagents, Lipids, Lipopolysaccharides, Male, Monocytes, Quantitative Trait Loci, Regulatory Sequences, Nucleic Acid, RNA, Double-Stranded, RNA, Messenger, Young Adult}, issn = {2041-1723}, doi = {10.1038/s41467-017-00366-1}, author = {Kim-Hellmuth, Sarah and Bechheim, Matthias and P{\"u}tz, Benno and Mohammadi, Pejman and N{\'e}d{\'e}lec, Yohann and Giangreco, Nicholas and Becker, Jessica and Kaiser, Vera and Fricker, Nadine and Beier, Esther and Boor, Peter and Castel, Stephane E and N{\"o}then, Markus M and Barreiro, Luis B and Pickrell, Joseph K and M{\"u}ller-Myhsok, Bertram and Lappalainen, Tuuli and Schumacher, Johannes and Hornung, Veit} } @article {33, title = {Genetics of coronary artery disease: discovery, biology and clinical translation.}, journal = {Nat Rev Genet}, volume = {18}, year = {2017}, month = {2017 Jun}, pages = {331-344}, abstract = {

Coronary artery disease is the leading global cause of mortality. Long recognized to be heritable, recent advances have started to unravel the genetic architecture of the disease. Common variant association studies have linked approximately 60 genetic loci to coronary risk. Large-scale gene sequencing efforts and functional studies have facilitated a better understanding of causal risk factors, elucidated underlying biology and informed the development of new therapeutics. Moving forwards, genetic testing could enable precision medicine approaches by identifying subgroups of patients at increased risk of coronary artery disease or those with a specific driving pathophysiology in whom a therapeutic or preventive approach would be most useful.

}, keywords = {Animals, Coronary Artery Disease, Humans, Precision Medicine, Translational Research, Biomedical}, issn = {1471-0064}, doi = {10.1038/nrg.2016.160}, author = {Khera, Amit V and Kathiresan, Sekar} } @article {23, title = {Genomic Patterns of De Novo Mutation in Simplex Autism.}, journal = {Cell}, volume = {171}, year = {2017}, month = {2017 Oct 19}, pages = {710-722.e12}, abstract = {

To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of \~{}1.5~{\texttimes} 10 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe~missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p~= 1.8~{\texttimes} 10, OR~= 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p~= 3~{\texttimes} 10), suggesting a path forward for genetically characterizing more complex cases of autism.

}, keywords = {Animals, Autistic Disorder, DNA Copy Number Variations, DNA Mutational Analysis, Female, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Mice, Polymorphism, Single Nucleotide}, issn = {1097-4172}, doi = {10.1016/j.cell.2017.08.047}, author = {Turner, Tychele N and Coe, Bradley P and Dickel, Diane E and Hoekzema, Kendra and Nelson, Bradley J and Zody, Michael C and Kronenberg, Zev N and Hormozdiari, Fereydoun and Raja, Archana and Pennacchio, Len A and Darnell, Robert B and Eichler, Evan E} } @article {16, title = {The impact of structural variation on human gene expression.}, journal = {Nat Genet}, volume = {49}, year = {2017}, month = {2017 May}, pages = {692-699}, abstract = {

Structural variants (SVs) are an important source of human genetic diversity, but their contribution to traits, disease and gene regulation remains unclear. We mapped cis expression quantitative trait loci (eQTLs) in 13 tissues via joint analysis of SVs, single-nucleotide variants (SNVs) and short insertion/deletion (indel) variants from deep whole-genome sequencing (WGS). We estimated that SVs are causal at 3.5-6.8\% of eQTLs-a substantially higher fraction than prior estimates-and that expression-altering SVs have larger effect sizes than do SNVs and indels. We identified 789 putative causal SVs predicted to directly alter gene expression: most (88.3\%) were noncoding variants enriched at enhancers and other regulatory elements, and 52 were linked to genome-wide association study loci. We observed a notable abundance of rare high-impact SVs associated with aberrant expression of nearby genes. These results suggest that comprehensive WGS-based SV analyses will increase the power of common- and rare-variant association studies.

}, keywords = {Algorithms, Chromosome Mapping, Gene Expression Regulation, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, INDEL Mutation, Linear Models, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Sequence Analysis, DNA}, issn = {1546-1718}, doi = {10.1038/ng.3834}, author = {Chiang, Colby and Scott, Alexandra J and Davis, Joe R and Tsang, Emily K and Li, Xin and Kim, Yungil and Hadzic, Tarik and Damani, Farhan N and Ganel, Liron and Montgomery, Stephen B and Battle, Alexis and Conrad, Donald F and Hall, Ira M} } @article {21, title = {Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.}, journal = {Circulation}, volume = {135}, year = {2017}, month = {2017 May 30}, pages = {2091-2101}, abstract = {

BACKGROUND: Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis.

METHODS: We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage).

RESULTS: Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44\% (95\% confidence interval [CI], 22-60; <0.001), whereas in all others, the relative risk reduction was 24\% (95\% CI, 8-37; =0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46\% versus 26\% in all others ( for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6\% (95\% CI, 2.0-5.1) among those in the high genetic risk group and 1.3\% (95\% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95\% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7\% higher (95\% CI, 2.2-17.8) burden of carotid plaque.

CONCLUSIONS: Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event.

CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.

}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Atherosclerosis, Cohort Studies, Cost of Illness, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Middle Aged, Multifactorial Inheritance, Primary Prevention, Risk Factors, Young Adult}, issn = {1524-4539}, doi = {10.1161/CIRCULATIONAHA.116.024436}, author = {Natarajan, Pradeep and Young, Robin and Stitziel, Nathan O and Padmanabhan, Sandosh and Baber, Usman and Mehran, Roxana and Sartori, Samantha and Fuster, Valentin and Reilly, Dermot F and Butterworth, Adam and Rader, Daniel J and Ford, Ian and Sattar, Naveed and Kathiresan, Sekar} } @article {15, title = {Concerted Genetic Function in Blood Traits.}, journal = {Cell}, volume = {167}, year = {2016}, month = {2016 Nov 17}, pages = {1167-1169}, abstract = {

The hematopoietic system plays a major role in human health. Two studies by Astle et~al. and Chen~et~al. published in this issue of Cell use genome-wide association and functional genomics approaches to provide deep insights into the role of genetic variants in hematological traits. We~discuss these discoveries and future strategies toward completing our understanding of the genetic basis for variation in human traits.

}, keywords = {Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Phenotype, Polymorphism, Single Nucleotide}, issn = {1097-4172}, doi = {10.1016/j.cell.2016.10.055}, author = {Kim-Hellmuth, Sarah and Lappalainen, Tuuli} } @article {8, title = {Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease.}, journal = {N Engl J Med}, volume = {375}, year = {2016}, month = {2016 Dec 15}, pages = {2349-2358}, abstract = {

BACKGROUND: Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown.

METHODS: Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women{\textquoteright}s Genome Health Study (WGHS), and 22,389 in the Malm{\"o} Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet.

RESULTS: The relative risk of incident coronary events was 91\% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95\% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46\% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95\% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7\% for an unfavorable lifestyle to 5.1\% for a favorable lifestyle in ARIC, from 4.6\% to 2.0\% in WGHS, and from 8.2\% to 5.3\% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.

CONCLUSIONS: Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50\% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.).

}, keywords = {Aged, Cohort Studies, Coronary Disease, Cross-Sectional Studies, Female, Genetic Predisposition to Disease, Healthy Lifestyle, Humans, Incidence, Male, Middle Aged, Multifactorial Inheritance, Patient Compliance, Polymorphism, Genetic, Risk}, issn = {1533-4406}, doi = {10.1056/NEJMoa1605086}, author = {Khera, Amit V and Emdin, Connor A and Drake, Isabel and Natarajan, Pradeep and Bick, Alexander G and Cook, Nancy R and Chasman, Daniel I and Baber, Usman and Mehran, Roxana and Rader, Daniel J and Fuster, Valentin and Boerwinkle, Eric and Melander, Olle and Orho-Melander, Marju and Ridker, Paul M and Kathiresan, Sekar} }