Analysis of protein-coding genetic variation in 60,706 humans

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 and Daniel G. MacArthur ()
Additional contact information
Monkol Lek: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Konrad J. Karczewski: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Eric V. Minikel: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Kaitlin E. Samocha: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Eric Banks: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Timothy Fennell: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Anne H. O’Donnell-Luria: Analytic and Translational Genetics Unit, Massachusetts General Hospital
James S. Ware: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Andrew J. Hill: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Beryl B. Cummings: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Taru Tukiainen: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Daniel P. Birnbaum: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Jack A. Kosmicki: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Laramie E. Duncan: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Karol Estrada: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Fengmei Zhao: Analytic and Translational Genetics Unit, Massachusetts General Hospital
James Zou: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Emma Pierce-Hoffman: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Joanne Berghout: Mouse Genome Informatics, Jackson Laboratory
David N. Cooper: Institute of Medical Genetics, Cardiff University
Nicole Deflaux: Google, Mountain View
Mark DePristo: Broad Institute of MIT and Harvard
Ron Do: Icahn School of Medicine at Mount Sinai
Jason Flannick: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Menachem Fromer: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Laura Gauthier: Broad Institute of MIT and Harvard
Jackie Goldstein: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Namrata Gupta: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Daniel Howrigan: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Adam Kiezun: Broad Institute of MIT and Harvard
Mitja I. Kurki: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Ami Levy Moonshine: Broad Institute of MIT and Harvard
Pradeep Natarajan: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Lorena Orozco: Immunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica
Gina M. Peloso: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Ryan Poplin: Broad Institute of MIT and Harvard
Manuel A. Rivas: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Valentin Ruano-Rubio: Broad Institute of MIT and Harvard
Samuel A. Rose: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Douglas M. Ruderfer: Icahn School of Medicine at Mount Sinai
Khalid Shakir: Broad Institute of MIT and Harvard
Peter D. Stenson: Institute of Medical Genetics, Cardiff University
Christine Stevens: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Brett P. Thomas: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Grace Tiao: Broad Institute of MIT and Harvard
Maria T. Tusie-Luna: Molecular Biology and Genomic Medicine Unit, Instituto Nacional de Ciencias Médicas y Nutrición
Ben Weisburd: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Hong-Hee Won: Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University
Dongmei Yu: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
David M. Altshuler: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Diego Ardissino: University Hospital
Michael Boehnke: University of Michigan
John Danesh: Strangeways Research Laboratory
Stacey Donnelly: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Roberto Elosua: Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute
Jose C. Florez: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Stacey B. Gabriel: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Gad Getz: Broad Institute of MIT and Harvard
Stephen J. Glatt: Psychiatric Genetic Epidemiology & Neurobiology Laboratory, State University of New York, Upstate Medical University
Christina M. Hultman: Karolinska Institutet
Sekar Kathiresan: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Markku Laakso: University of Eastern Finland and Kuopio University Hospital
Steven McCarroll: Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard
Mark I. McCarthy: Wellcome Trust Centre for Human Genetics, University of Oxford
Dermot McGovern: Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center
Ruth McPherson: Atherogenomics Laboratory, University of Ottawa Heart Institute
Benjamin M. Neale: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Aarno Palotie: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Shaun M. Purcell: Icahn School of Medicine at Mount Sinai
Danish Saleheen: Perelman School of Medicine at the University of Pennsylvania
Jeremiah M. Scharf: Program in Medical and Population Genetics, Broad Institute of MIT and Harvard
Pamela Sklar: Icahn School of Medicine at Mount Sinai
Patrick F. Sullivan: University of North Carolina
Jaakko Tuomilehto: University of Helsinki
Ming T. Tsuang: University of California
Hugh C. Watkins: Wellcome Trust Centre for Human Genetics, University of Oxford
James G. Wilson: University of Mississippi Medical Center
Mark J. Daly: Analytic and Translational Genetics Unit, Massachusetts General Hospital
Daniel G. MacArthur: Analytic and Translational Genetics Unit, Massachusetts General Hospital

Nature, 2016, vol. 536, issue 7616, 285-291

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature19057

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