Year: 2016
Type: article
Study design: Observational Study
Abstract: Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human ‘knockout’ variants in protein-coding genes. Exome sequencing data from 60,706 people of diverse geographic ancestry is presented, providing insight into genetic variation across populations, and illuminating the relationship between DNA variants and human disease. As part of the Exome Aggregation Consortium (ExAC) project, Daniel MacArthur and colleagues report on the generation and analysis of high-quality exome sequencing data from 60,706 individuals of diverse ancestry. This provides the most comprehensive catalogue of human protein-coding genetic variation to date, yielding unprecedented resolution for the analysis of very rare variants across multiple human populations. The catalogue is freely accessible and provides a critical reference panel for the clinical interpretation of genetic variants and the discovery of disease-related genes.
Source: Nature
DOI: 10.1038/nature19057
Authors: Monkol Lek, Konrad J. Karczewski, Eric V. Minikel, Kaitlin E. Samocha, Eric Banks, Timothy Fennell, Anne H. O’Donnell-Luria, James S. Ware, Andrew J. Hill, Beryl B. Cummings, Taru Tukiainen, Daniel P. Birnbaum, Jack A. Kosmicki, Laramie E. Duncan, Karol Estrada, Fengmei Zhao, James Zou, Emma Pierce-Hoffman, Joanne Berghout, David N. Cooper, Nicole Deflaux, Mark DePristo, Ron Do, Jason Flannick, Menachem Fromer, Laura Gauthier, Jackie Goldstein, Namrata Gupta, Daniel Howrigan, Adam Kiezun, Mitja I. Kurki, Ami Levy Moonshine, Pradeep Natarajan, Lorena Orozco, Gina M. Peloso, Ryan Poplin, Manuel A. Rivas, Valentin Ruano-Rubio, Samuel A. Rose, Douglas M. Ruderfer, Khalid Shakir, Peter D. Stenson, Christine Stevens, Brett P. Thomas, Grace Tiao, Maria T. Tusie-Luna, Ben Weisburd, Hong-Hee Won, Dongmei Yu, David M. Altshuler, Diego Ardissino, Michael Boehnke, John Danesh, Stacey Donnelly, Roberto Elosua, Jose C. Florez, Stacey B. Gabriel, Gad Getz, Stephen J. Glatt, Christina M. Hultman, Sekar Kathiresan, Markku Laakso, Steven McCarroll, Mark I. McCarthy, Dermot McGovern, Ruth McPherson, Benjamin M. Neale, Aarno Palotie, Shaun M. Purcell, Danish Saleheen, Jeremiah M. Scharf, Pamela Sklar, Patrick F. Sullivan, Jaakko Tuomilehto, Ming T. Tsuang, Hugh C. Watkins, James G. Wilson, Mark J. Daly, Daniel G. MacArthur
Institutions: Broad Institute, The University of Sydney, Children's Hospital at Westmead, Massachusetts General Hospital, Harvard University, Stanley Center for Psychiatric Research, Boston Children's Hospital, Royal Brompton Hospital, NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Imperial College London, University of Washington, University of Arizona, Jackson Laboratory, Cardiff University, Google (United States), Icahn School of Medicine at Mount Sinai, National Institute of Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Samsung Medical Center, Sungkyunkwan University, Vertex Pharmaceuticals (United States), University of Michigan, University of Cambridge, Hospital Del Mar, Hospital del Mar Research Institute, SUNY Upstate Medical University, Karolinska Institutet, University of Eastern Finland, Kuopio University Hospital, Centre for Human Genetics, University of Oxford, NIHR Oxford Biomedical Research Centre, Oxford Centre for Diabetes, Endocrinology and Metabolism, Cedars-Sinai Medical Center, Ottawa Heart Institute, University of Helsinki, Institute for Molecular Medicine Finland, Center for Non-Communicable Diseases, University of Pennsylvania, University of North Carolina at Chapel Hill, University of California San Diego, University of Mississippi Medical Center
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: ACMG Foundation for Genetic and Genomic Medicine, Wellcome Trust, National Institute for Health and Care Research, British Heart Foundation, European Commission, Cambridge University Hospitals, National Institutes of Health, U.S. Public Health Service, Pfizer Foundation, Canadian Institutes of Health Research, Medical Research Council, National Health and Medical Research Council, National Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Human Genome Research Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: Multiethnic Study of Type 2 Diabetes Genes, G112182703, Identifying T2D Variants by DNA Sequencing in Multiethnic Samples, G1303440240, 1/2 A Large-Scale Schizophrenia Association Study in Sweden, 2/2-Expanding Rapid Ascertainment Networks Of Schizophrenia Families In Taiwan, G1870499941, Next-Generation Disease Association Analyses: Low pass Sequencing and High Density SNP genotyping for type 2 diabetes ., G1987718741, Large Scale Sequencing and Analysis of Genomes, G2013484569, G2050459141, DIABETES AND CARDIOVASCULAR RISK IN MEXICO CITY, G2129077002, Identification and Replication of Type 2 Diabetes Genes in Mexican Americans, Identification of epigenetic markers underlying increased risk of T2D in South Asians, G2474488143, NIHR Senior Investigator Award, Characterising causal alleles for common disease., Advancing Tourette Syndrome genetics using bioinformatics and genome biology, Identifying Genes for Type 2 Diabetes: FUSION, G2968709716, Discovery of Functional Variants in Type 2 Diabetes Genes in Mexican Americans, G3052756085, White Matter Abnormalities in Schizophrenia, Pharmacogenomic, genetic and trial-based studies of lipid-modifying therapies and vascular risk, G3245635901, G328833407, G3395363768, Mouse Genome Database, 1/2 Expanding Rapid Ascertainment Networks Of Schizophrenia Families In Taiwan, The Human Knockout Project: systematic discovery of loss-of-function variants in humans, Identifying variants causal for Type 2 Diabetes in Major human populations, G4198439741, G4404085764, G4608159596, A Genetic Linkage Study of GTS, Whole genome sequencing of bipolar disorder and schizophrenia, 1/4 Psychiatric GWAS Consortium: Genomic Follow-up Next-Gen Seq & Genotyping, Discovering lipoprotein lipase pathway variants that protect against CHD, G5618924097, MRC Centre for Neuropsychiatric Genetics and Genomics, NIHR Senior Investigator Award, G6089286521, G6248760688, Low-Pass Sequencing and High-Density SNP Genotyping for Type 2 Diabetes, G6362460185, NIHR Senior Investigator Award, EPIC-CVD: Individualised CVD risk assessment: tailoring targeted and cost-effective approaches to Europe's diverse populations, Einstein's Nathan Shock Center of Excellence in Basic Biology of Aging, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G7113137867, G7163651447, G7226679574, The BHF Chair of Epidemiology and Medicine, G7338882857, The Impact of Human Gene Knockouts in Type 2 Diabetes and Related Traits, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application (renewal). (Joint funding with MRC), Using genetics to explore the pathophysiology of cerebral small vessel disease. 15, Annotation and interpretation of loss-of-function polymorphisms in human genomes, NIHR Senior Investigator Award, Center for Genome Interpretation, 2/2 Large-Scale Genetic Studies of Schizophrenia in Sweden, G8163728846, G8345303874, Discovery of Mendelian Dyslipidemia and Heart Attack Genes Using Exome Sequencing, G8585681489, NIHR Senior Investigator Award, 2/4-Psychiatric GWAS Consortium: Genomic Follow-Up Next-Gen Sequencing & Genotypi, Genomic dissection of inherited cardiomyopathies: identifying alleles, genes and mechanisms, for patient stratification., Michigan Diabetes Research Center (MDRC), Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital, Integrated, Multidisciplinary Training in Cardiovascular Research, Identifying Genes for Type 2 Diabetes: FUSION, Large-scale integrative studies of risk factors in coronary heart disease: from discovery to application
OpenAlex ID: W2256016639