@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 {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 {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 {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 {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 {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 {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 {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 {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 {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 {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 {54, title = {Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 Sep}, pages = {2135-2144}, abstract = {

PURPOSE: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.

METHODS: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap).

RESULTS: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by~Multiplex Ligation-dependent Probe Amplification (MLPA).

CONCLUSION: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0475-4}, author = {Chiang, Theodore and Liu, Xiuping and Wu, Tsung-Jung and Hu, Jianhong and Sedlazeck, Fritz J and White, Simon and Schaid, Daniel and Andrade, Mariza de and Jarvik, Gail P and Crosslin, David and Stanaway, Ian and Carrell, David S and Connolly, John J and Hakonarson, Hakon and Groopman, Emily E and Gharavi, Ali G and Fedotov, Alexander and Bi, Weimin and Leduc, Magalie S and Murdock, David R and Jiang, Yunyun and Meng, Linyan and Eng, Christine M and Wen, Shu and Yang, Yaping and Muzny, Donna M and Boerwinkle, Eric and Salerno, William and Venner, Eric and Gibbs, Richard A} } @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 {66, title = {Identification and Validation of Hematoma Volume Cutoffs in Spontaneous, Supratentorial Deep Intracerebral Hemorrhage.}, journal = {Stroke}, volume = {50}, year = {2019}, month = {2019 Aug}, pages = {2044-2049}, abstract = {

Background and Purpose- Clinical trials in spontaneous intracerebral hemorrhage (ICH) have used volume cutoffs as inclusion criteria to select populations in which the effects of interventions are likely to be the greatest. However, optimal volume cutoffs for predicting poor outcome in deep locations (thalamus versus basal ganglia) are unknown. Methods- We conducted a 2-phase study to determine ICH volume cutoffs for poor outcome (modified Rankin Scale score of 4-6) in the thalamus and basal ganglia. Cutoffs with optimal sensitivity and specificity for poor outcome were identified in the ERICH ([Ethnic/Racial Variations of ICH] study; derivation cohort) using receiver operating characteristic curves. The cutoffs were then validated in the ATACH-2 trial (Antihypertensive Treatment of Acute Cerebral Hemorrhage-2) by comparing the c-statistic of regression models for outcome (including dichotomized volume) in the validation cohort. Results- Of the 3000 patients enrolled in ERICH, 1564 (52\%) had deep ICH, of whom 1305 (84\%) had complete neuroimaging and outcome data (660 thalamic and 645 basal ganglia hemorrhages). Receiver operating characteristic curve analysis identified 8 mL in thalamic (area under the curve, 0.79; sensitivity, 73\%; specificity, 78\%) and 18 mL in basal ganglia ICH (area under the curve, 0.79; sensitivity, 70\%; specificity, 83\%) as optimal cutoffs for predicting poor outcome. The validation cohort included 834 (84\%) patients with deep ICH and complete neuroimaging data enrolled in ATACH-2 (353 thalamic and 431 basal ganglia hemorrhages). In thalamic ICH, the c-statistic of the multivariable outcome model including dichotomized ICH volume was 0.80 (95\% CI, 0.75-0.85) in the validation cohort. For basal ganglia ICH, the c-statistic was 0.81 (95\% CI, 0.76-0.85) in the validation cohort. Conclusions- Optimal hematoma volume cutoffs for predicting poor outcome in deep ICH vary by the specific deep brain nucleus involved. Utilization of location-specific volume cutoffs may improve clinical trial design by targeting deep ICH patients that will obtain maximal benefit from candidate therapies.

}, issn = {1524-4628}, doi = {10.1161/STROKEAHA.118.023851}, author = {Leasure, Audrey C and Sheth, Kevin N and Comeau, Mary and Aldridge, Chad and Worrall, Bradford B and Vashkevich, Anastasia and Rosand, Jonathan and Langefeld, Carl and Moomaw, Charles J and Woo, Daniel and Falcone, Guido J} } @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 {37, title = {Accurate detection of complex structural variations using single-molecule sequencing.}, journal = {Nat Methods}, volume = {15}, year = {2018}, month = {2018 Jun}, pages = {461-468}, abstract = {

Structural variations are the greatest source of genetic variation, but they remain poorly understood because of technological limitations. Single-molecule long-read sequencing has the potential to dramatically advance the field, although high error rates are a challenge with existing methods. Addressing this need, we introduce open-source methods for long-read alignment (NGMLR; https://github.com/philres/ngmlr ) and structural variant identification (Sniffles; https://github.com/fritzsedlazeck/Sniffles ) that provide unprecedented sensitivity and precision for variant detection, even in repeat-rich regions and for complex nested events that can have substantial effects on human health. In several long-read datasets, including healthy and cancerous human genomes, we discovered thousands of novel variants and categorized systematic errors in short-read approaches. NGMLR and Sniffles can automatically filter false events and operate on low-coverage data, thereby reducing the high costs that have hindered the application of long reads in clinical and research settings.

}, keywords = {DNA Mutational Analysis, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA}, issn = {1548-7105}, doi = {10.1038/s41592-018-0001-7}, author = {Sedlazeck, Fritz J and Rescheneder, Philipp and Smolka, Moritz and Fang, Han and Nattestad, Maria and von Haeseler, Arndt and Schatz, Michael C} } @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 {36, title = {Characterization and remediation of sample index swaps by non-redundant dual indexing on massively parallel sequencing platforms.}, journal = {BMC Genomics}, volume = {19}, year = {2018}, month = {2018 May 08}, pages = {332}, abstract = {

BACKGROUND: Here we present an in-depth characterization of the mechanism of sequencer-induced sample contamination due to the phenomenon of index swapping that impacts Illumina sequencers employing patterned flow cells with Exclusion Amplification (ExAmp) chemistry (HiSeqX, HiSeq4000, and NovaSeq). We also present a remediation method that minimizes the impact of such swaps.

RESULTS: Leveraging data collected over a two-year period, we demonstrate the widespread prevalence of index swapping in patterned flow cell data. We calculate mean swap rates across multiple sample preparation methods and sequencer models, demonstrating that different library methods can have vastly different swapping rates and that even non-ExAmp chemistry instruments display trace levels of index swapping. We provide methods for eliminating sample data cross contamination by utilizing non-redundant dual indexing for complete filtering of index swapped reads, and share the sequences for 96 non-combinatorial dual indexes we have validated across various library preparation methods and sequencer models. Finally, using computational methods we provide a greater insight into the mechanism of index swapping.

CONCLUSIONS: Index swapping in pooled libraries is a prevalent phenomenon that we observe at a rate of 0.2 to 6\% in all sequencing runs on HiSeqX, HiSeq 4000/3000, and NovaSeq. Utilizing non-redundant dual indexing allows for the removal (flagging/filtering) of these swapped reads and eliminates swapping induced sample contamination, which is critical for sensitive applications such as RNA-seq, single cell, blood biopsy using circulating tumor DNA, or clinical sequencing.

}, keywords = {DNA, Gene Library, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, Sequence Analysis, DNA}, issn = {1471-2164}, doi = {10.1186/s12864-018-4703-0}, author = {Costello, Maura and Fleharty, Mark and Abreu, Justin and Farjoun, Yossi and Ferriera, Steven and Holmes, Laurie and Granger, Brian and Green, Lisa and Howd, Tom and Mason, Tamara and Vicente, Gina and Dasilva, Michael and Brodeur, Wendy and DeSmet, Timothy and Dodge, Sheila and Lennon, Niall J and Gabriel, Stacey} } @article {39, title = {Differential 3{\textquoteright} Processing of Specific Transcripts Expands Regulatory and Protein Diversity Across Neuronal Cell Types.}, journal = {Elife}, volume = {7}, year = {2018}, month = {2018 Mar 26}, abstract = {

Alternative polyadenylation (APA) regulates mRNA translation, stability, and protein localization. However, it is unclear to what extent APA regulates these processes uniquely in specific cell types. Using a new technique, cTag-PAPERCLIP, we discovered significant differences in APA between the principal types of mouse cerebellar neurons, the Purkinje and granule cells, as well as between proliferating and differentiated granule cells. Transcripts that differed in APA in these comparisons were enriched in key neuronal functions and many differed in coding sequence in addition to 3{\textquoteright}UTR length. We characterize , a transcript that shifted from expressing a short 3{\textquoteright}UTR isoform to a longer one during granule cell differentiation. We show that regulates granule cell precursor proliferation and that its long 3{\textquoteright}UTR isoform is targeted by miR-124, contributing to its downregulation during development. Our findings provide insight into roles for APA in specific cell types and establish a platform for further functional studies.

}, issn = {2050-084X}, doi = {10.7554/eLife.34042}, author = {Jereb, Sa{\v s}a and Hwang, Hun-Way and Van Otterloo, Eric and Govek, Eve-Ellen and Fak, John J and Yuan, Yuan and Hatten, Mary E and Darnell, Robert B} } @article {46, title = {Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk.}, journal = {Nat Genet}, volume = {50}, year = {2018}, month = {2018 Sep}, pages = {1327-1334}, abstract = {

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed {\textquoteright}variable penetrance{\textquoteright}. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.

}, issn = {1546-1718}, doi = {10.1038/s41588-018-0192-y}, author = {Castel, Stephane E and Cervera, Alejandra and Mohammadi, Pejman and Aguet, Fran{\c c}ois and Reverter, Ferran and Wolman, Aaron and Guigo, Roderic and Iossifov, Ivan and Vasileva, Ana and Lappalainen, Tuuli} } @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 {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 {27, title = {Type 2 Diabetes Variants Disrupt Function of SLC16A11 through Two Distinct Mechanisms.}, journal = {Cell}, volume = {170}, year = {2017}, month = {2017 Jun 29}, pages = {199-212.e20}, abstract = {

Type 2 diabetes (T2D) affects Latinos at twice the~rate~seen in populations of European descent. We~recently identified a risk haplotype spanning SLC16A11 that explains \~{}20\% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at~this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.

}, keywords = {Basigin, Cell Membrane, Chromosomes, Human, Pair 17, Diabetes Mellitus, Type 2, Gene Knockdown Techniques, Haplotypes, Hepatocytes, Heterozygote, Histone Code, Humans, Liver, Models, Molecular, Monocarboxylic Acid Transporters}, issn = {1097-4172}, doi = {10.1016/j.cell.2017.06.011}, author = {Rusu, Victor and Hoch, Eitan and Mercader, Josep M and Tenen, Danielle E and Gymrek, Melissa and Hartigan, Christina R and DeRan, Michael and von Grotthuss, Marcin and Fontanillas, Pierre and Spooner, Alexandra and Guzman, Gaelen and Deik, Amy A and Pierce, Kerry A and Dennis, Courtney and Clish, Clary B and Carr, Steven A and Wagner, Bridget K and Schenone, Monica and Ng, Maggie C Y and Chen, Brian H and Centeno-Cruz, Federico and Zerrweck, Carlos and Orozco, Lorena and Altshuler, David M and Schreiber, Stuart L and Florez, Jose C and Jacobs, Suzanne B R and Lander, Eric S} }