@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 {134, title = {The Genetic Control of Stoichiometry Underlying Autism.}, journal = {Annu Rev Neurosci}, volume = {43}, year = {2020}, month = {2020 07 08}, pages = {509-533}, abstract = {

Autism is a common and complex neurologic disorder whose scientific underpinnings have begun to be established in the past decade. The essence of this breakthrough has been a focus on families, where genetic analyses are strongest, versus large-scale, case-control studies. Autism genetics has progressed in parallel with technology, from analyses of copy number variation to whole-exome sequencing (WES) and whole-genome sequencing (WGS). Gene mutations causing complete loss of function account for perhaps one-third of cases, largely detected through WES. This limitation has increased interest in understanding the regulatory variants of genes that contribute in more subtle ways to the disorder. Strategies combining biochemical analysis of gene regulation, WGS analysis of the noncoding genome, and machine learning have begun to succeed. The emerging picture is that careful control of the amounts of transcription, mRNA, and proteins made by key brain genes-stoichiometry-plays a critical role in defining the clinical features of autism.

}, issn = {1545-4126}, doi = {10.1146/annurev-neuro-100119-024851}, author = {Darnell, Robert B} } @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 {97, title = {The GTEx Consortium atlas of genetic regulatory effects across human tissues.}, journal = {Science}, volume = {369}, year = {2020}, month = {2020 09 11}, pages = {1318-1330}, abstract = {

The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.

}, keywords = {Datasets as Topic, Disease, Female, Gene Expression Regulation, Genome-Wide Association Study, Humans, Male, Organ Specificity, Quantitative Trait Loci, Sequence Analysis, RNA}, issn = {1095-9203}, doi = {10.1126/science.aaz1776} } @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 {83, title = {Genetic regulatory variation in populations informs transcriptome analysis in rare disease.}, journal = {Science}, volume = {366}, year = {2019}, month = {2019 10 18}, pages = {351-356}, abstract = {

Transcriptome data can facilitate the interpretation of the effects of rare genetic variants. Here, we introduce ANEVA (analysis of expression variation) to quantify genetic variation in gene dosage from allelic expression (AE) data in a population. Application of ANEVA to the Genotype-Tissues Expression (GTEx) data showed that this variance estimate is robust and correlated with selective constraint in a gene. Using these variance estimates in a dosage outlier test (ANEVA-DOT) applied to AE data from 70 Mendelian muscular disease patients showed accuracy in detecting genes with pathogenic variants in previously resolved cases and led to one confirmed and several potential new diagnoses. Using our reference estimates from GTEx data, ANEVA-DOT can be incorporated in rare disease diagnostic pipelines to use RNA-sequencing data more effectively.

}, issn = {1095-9203}, doi = {10.1126/science.aay0256}, author = {Mohammadi, Pejman and Castel, Stephane E and Cummings, Beryl B and Einson, Jonah and Sousa, Christina and Hoffman, Paul and Donkervoort, Sandra and Jiang, Zhuoxun and Mohassel, Payam and Foley, A Reghan and Wheeler, Heather E and Im, Hae Kyung and Bonnemann, Carsten G and MacArthur, Daniel G and Lappalainen, Tuuli} } @article {67, title = {Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 Jul}, pages = {1611-1620}, abstract = {

PURPOSE: To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD).

METHODS: GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons.

RESULTS: We found that 40.8\% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1\% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9\%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family.

CONCLUSION: The study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.

}, issn = {1530-0366}, doi = {10.1038/s41436-018-0380-2}, author = {Guo, Hui and Duyzend, Michael H and Coe, Bradley P and Baker, Carl and Hoekzema, Kendra and Gerdts, Jennifer and Turner, Tychele N and Zody, Michael C and Beighley, Jennifer S and Murali, Shwetha C and Nelson, Bradley J and Bamshad, Michael J and Nickerson, Deborah A and Bernier, Raphael A and Eichler, Evan E} } @article {51, title = {Genome-wide patterns of transposon proliferation in an evolutionary young hybrid fish.}, journal = {Mol Ecol}, volume = {28}, year = {2019}, month = {2019 Mar}, pages = {1491-1505}, abstract = {

Hybridization can induce transposons to jump into new genomic positions, which may result in their accumulation across the genome. Alternatively, transposon copy numbers may increase through nonallelic (ectopic) homologous recombination in highly repetitive regions of the genome. The relative contribution of transposition bursts versus recombination-based mechanisms to evolutionary processes remains unclear because studies on transposon dynamics in natural systems are rare. We assessed the genomewide distribution of transposon insertions in a young hybrid lineage ("invasive Cottus", n~=~11) and its parental species Cottus rhenanus (n~=~17) and Cottus perifretum(n~=~9) using a reference genome assembled from long single molecule pacbio reads. An inventory of transposable elements was reconstructed from the same data and annotated. Transposon copy numbers in the hybrid lineage increased in 120 (15.9\%) out of 757 transposons studied here. The copy number increased on average by 69\% (range: 10\%-197\%). Given the age of the hybrid lineage, this suggests that they have proliferated within a few hundred generations since admixture began. However, frequency spectra of transposon insertions revealed no increase in novel and rare insertions across assembled parts of the genome. This implies that transposons were added to repetitive regions of the genome that remain difficult to assemble. Future studies will need to evaluate whether recombination-based mechanisms rather than genomewide transposition may explain the majority of the recent transposon proliferation in the hybrid lineage. Irrespectively of the underlying mechanism, the observed overabundance in repetitive parts of the genome suggests that gene-rich regions are unlikely to be directly affected.

}, issn = {1365-294X}, doi = {10.1111/mec.14969}, author = {Dennenmoser, Stefan and Sedlazeck, Fritz J and Schatz, Michael C and Altm{\"u}ller, Janine and Zytnicki, Matthias and Nolte, Arne W} } @article {64, title = {Genomic Analysis in the Age of Human Genome Sequencing.}, journal = {Cell}, volume = {177}, year = {2019}, month = {2019 Mar 21}, pages = {70-84}, abstract = {

Affordable genome sequencing technologies promise to revolutionize the field of human genetics by enabling comprehensive studies that interrogate all classes of genome variation, genome-wide, across the entire allele frequency spectrum. Ongoing projects worldwide are sequencing many thousands-and soon millions-of human genomes as part of various gene mapping studies, biobanking efforts, and clinical programs. However, while genome sequencing data production has become routine, genome analysis and interpretation remain challenging endeavors with many limitations and caveats. Here, we review the current state of technologies for genetic variant discovery, genotyping, and functional interpretation and discuss the prospects for future advances. We focus on germline variants discovered by whole-genome sequencing, genome-wide functional genomic approaches for predicting and measuring variant functional effects, and implications for studies of common and rare human disease.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2019.02.032}, author = {Lappalainen, Tuuli and Scott, Alexandra J and Brandt, Margot and Hall, Ira M} } @article {31, title = {Genetic variants in microRNA genes and targets associated with cardiovascular disease risk factors in the African-American population.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jan}, pages = {85-94}, abstract = {

The purpose of this study is to identify microRNA (miRNA) related polymorphism, including single nucleotide variants (SNVs) in mature miRNA-encoding sequences or in miRNA-target sites, and their association with cardiovascular disease (CVD) risk factors in African-American population. To achieve our objective, we examined 1900 African-Americans from the Atherosclerosis Risk in Communities study using SNVs identified from whole-genome sequencing data. A total of 971 SNVs found in 726 different mature miRNA-encoding sequences and 16,057 SNVs found in the three prime untranslated region (3{\textquoteright}UTR) of 3647 protein-coding genes were identified and interrogated their associations with 17 CVD risk factors. Using single-variant-based approach, we found 5 SNVs in miRNA-encoding sequences to be associated with serum Lipoprotein(a) [Lp(a)], high-density lipoprotein (HDL) or triglycerides, and 2 SNVs in miRNA-target sites to be associated with Lp(a) and HDL, all with false discovery rates of 5\%. Using a gene-based approach, we identified 3 pairs of associations between gene NSD1 and platelet count, gene HSPA4L and cardiac troponin T, and gene AHSA2 and magnesium. We successfully validated the association between a variant specific to African-American population, NR_039880.1:n.18A>C, in mature hsa-miR-4727-5p encoding sequence and serum HDL level in an independent sample of 2135 African-Americans. Our study provided candidate miRNAs and their targets for further investigation of their potential contribution to ethnic disparities in CVD risk factors.

}, keywords = {3{\textquoteright} Untranslated Regions, Adult, Black or African American, Cardiovascular Diseases, Female, Genetic Predisposition to Disease, Genotyping Techniques, Humans, Male, MicroRNAs, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors, Whole Genome Sequencing}, issn = {1432-1203}, doi = {10.1007/s00439-017-1858-8}, author = {Li, Chang and Grove, Megan L and Yu, Bing and Jones, Barbara C and Morrison, Alanna and Boerwinkle, Eric and Liu, Xiaoming} } @article {41, title = {Genetics of the extracellular matrix in aortic aneurysmal diseases.}, journal = {Matrix Biol}, volume = {71-72}, year = {2018}, month = {2018 10}, pages = {128-143}, abstract = {

Aortic aneurysms are morbid conditions that can lead to rupture or dissection and are categorized as thoracic (TAA) or abdominal aortic aneurysms (AAA) depending on their location. While AAA shares overlapping risk factors with atherosclerotic cardiovascular disease, TAA exhibits strong heritability. Human genetic studies in the past two decades have successfully identified numerous genes involved in both familial and sporadic forms of aortic aneurysm. In this review we will discuss the genetic basis of aortic aneurysm, focusing on the extracellular matrix and how insights from these studies have informed our understanding of human biology and disease pathogenesis.

}, issn = {1569-1802}, doi = {10.1016/j.matbio.2018.04.005}, author = {Lin, Chien-Jung and Lin, Chieh-Yu and Stitziel, Nathan O} } @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 {29, title = {Genetic association studies in cardiovascular diseases: Do we have enough power?}, journal = {Trends Cardiovasc Med}, volume = {27}, year = {2017}, month = {2017 Aug}, pages = {397-404}, abstract = {

Genetic association studies have a long history of delivering insightful results for cardiovascular disease (CVD) research. Beginning with early candidate gene studies, to genome-wide association studies, and now on to newer whole-genome sequencing studies, research in human genetics has enriched our understanding of the pathobiology of CVD. As these studies continue to expand, the issue of statistical power plays an important role in study design as well as the interpretation of results. We provide an overview of the component parts that determine statistical power and preview the future of CVD genetic association studies through this lens.

}, keywords = {Cardiovascular Diseases, Data Accuracy, Data Interpretation, Statistical, Genetic Association Studies, Genetic Markers, Genetic Predisposition to Disease, Genetic Variation, Humans, Phenotype, Reproducibility of Results, Research Design, Risk Assessment, Risk Factors}, issn = {1873-2615}, doi = {10.1016/j.tcm.2017.03.005}, author = {Auer, Paul L and Stitziel, Nathan O} } @article {32, title = {Genetic effects on gene expression across human tissues.}, journal = {Nature}, volume = {550}, year = {2017}, month = {2017 Oct 11}, pages = {204-213}, abstract = {

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

}, keywords = {Alleles, Chromosomes, Human, Disease, Female, Gene Expression Profiling, Gene Expression Regulation, Genetic Variation, Genome, Human, Genotype, Humans, Male, Organ Specificity, Quantitative Trait Loci}, issn = {1476-4687}, doi = {10.1038/nature24277}, author = {Battle, Alexis and Brown, Christopher D and Engelhardt, Barbara E and Montgomery, Stephen B} } @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 {19, title = {Genome-wide profiling of heritable and de novo STR variations.}, journal = {Nat Methods}, volume = {14}, year = {2017}, month = {2017 Jun}, pages = {590-592}, abstract = {

Short tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases, population genetics applications, and forensic casework. However, it has proven problematic to genotype STRs from high-throughput sequencing data. Here, we describe HipSTR, a novel haplotype-based method for robustly genotyping and phasing STRs from Illumina sequencing data, and we report a genome-wide analysis and validation of de novo STR mutations. HipSTR is freely available at https://hipstr-tool.github.io/HipSTR.

}, keywords = {Algorithms, Chromosome Mapping, DNA Fingerprinting, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Microsatellite Repeats, Sequence Alignment, Sequence Analysis, DNA, Software}, issn = {1548-7105}, doi = {10.1038/nmeth.4267}, author = {Willems, Thomas and Zielinski, Dina and Yuan, Jie and Gordon, Assaf and Gymrek, Melissa and Erlich, Yaniv} } @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 {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} } @article {10, title = {Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Jan 07}, pages = {58-74}, abstract = {

We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.

}, keywords = {Autistic Disorder, DNA, Exome, Female, Genome, Human, Humans, Male, Pedigree, Polymorphism, Single Nucleotide}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.11.023}, author = {Turner, Tychele N and Hormozdiari, Fereydoun and Duyzend, Michael H and McClymont, Sarah A and Hook, Paul W and Iossifov, Ivan and Raja, Archana and Baker, Carl and Hoekzema, Kendra and Stessman, Holly A and Zody, Michael C and Nelson, Bradley J and Huddleston, John and Sandstrom, Richard and Smith, Joshua D and Hanna, David and Swanson, James M and Faustman, Elaine M and Bamshad, Michael J and Stamatoyannopoulos, John and Nickerson, Deborah A and McCallion, Andrew S and Darnell, Robert and Eichler, Evan E} }