ArticleNature2016
Analysis of protein-coding genetic variation in 60,706 humans.
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Who cites it
6,078 citing papers in PubMed, 1 synthesis or guideline pooled it.
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6,018 more citing papers are in PubMed but not listed here.
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Authors and funding
80 authors.
Monkol LekAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Konrad J KarczewskiAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Eric V MinikelAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Kaitlin E SamochaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Eric BanksProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Timothy FennellProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Anne H O'Donnell-LuriaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
James S WareProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Andrew J HillAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Beryl B CummingsAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Taru TukiainenAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Daniel P BirnbaumProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Jack A KosmickiAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Laramie E DuncanAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Karol EstradaAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Fengmei ZhaoAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
James ZouProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Emma Pierce-HoffmanAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Joanne BerghoutMouse Genome Informatics, Jackson Laboratory, Bar Harbor, Maine 04609, USA.
David N CooperInstitute of Medical Genetics, Cardiff University, Cardiff CF10 3XQ, UK.
Nicole DeflauxGoogle, Mountain View, California 94043, USA.
Mark DePristoBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Ron DoDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Jason FlannickProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Menachem FromerAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Laura GauthierBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Jackie GoldsteinAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Namrata GuptaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Daniel HowriganAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Adam KiezunBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Mitja I KurkiProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Ami Levy MoonshineBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Pradeep NatarajanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Lorena OrozcoImmunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genómica, Mexico City 14610, Mexico.
Gina M PelosoProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Ryan PoplinBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Manuel A RivasProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Valentin Ruano-RubioBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Samuel A RoseStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Douglas M RuderferDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Khalid ShakirBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Peter D StensonInstitute of Medical Genetics, Cardiff University, Cardiff CF10 3XQ, UK.
Christine StevensProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Brett P ThomasAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Grace TiaoBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Maria T Tusie-LunaMolecular Biology and Genomic Medicine Unit, Instituto Nacional de Ciencias Médicas y Nutrición, Mexico City 14080, Mexico.
Ben WeisburdProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Hong-Hee WonSamsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.
Dongmei YuStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
David M AltshulerProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Diego ArdissinoDepartment of Cardiology, University Hospital, 43100 Parma, Italy.
Michael BoehnkeDepartment of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.
John DaneshDepartment of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge CB1 8RN, UK.
Stacey DonnellyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Roberto ElosuaCardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute, 08003 Barcelona, Spain.
Jose C FlorezProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Stacey B GabrielProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Gad GetzBroad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Stephen J GlattPsychiatric Genetic Epidemiology &Neurobiology Laboratory, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.
Christina M HultmanDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Sekar KathiresanProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Markku LaaksoDepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, 70211 Kuopio, Finland.
Steven McCarrollStanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Mark I McCarthyWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.
Dermot McGovernInflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Ruth McPhersonAtherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Ontario K1Y 4W7, Canada.
Benjamin M NealeAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Aarno PalotieAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Shaun M PurcellDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Danish SaleheenDepartment of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Jeremiah M ScharfProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
Pamela SklarDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
Patrick F SullivanDepartment of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Jaakko TuomilehtoDepartment of Public Health, University of Helsinki, 00100 Helsinki, Finland.
Ming T TsuangDepartment of Psychiatry, University of California, San Diego, California 92093, USA.
Hugh C WatkinsWellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX1 2JD, UK.
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
Mark J DalyAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Daniel G MacArthurAnalytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Exome Aggregation Consortium
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MMouse Genome DatabaseU41HG000330 · NHGRI · JACKSON LABORATORY · PI BLAKE, JUDITH A, BULT, CAROL J · 2011 to 2020
$45.5MPilot & Feasibility ProgramP30DK043351 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI RAYMOND T CHUNG · 1991 to 2026
$35.3MRegional Pilot And Feasibility Study Grants ProgramP30DK020572 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI Mehboob A Hussain · 2013 to 2026
$24.3MWhite Matter Abnormalities in SchizophreniaP50MH066392 · NIMH · MOUNT SINAI SCHOOL OF MEDICINE OF NYU · PI BUXBAUM, JOSEPH D. · 2002 to 2012
$18.6MLow-Pass Sequencing and High-Density SNP Genotyping for Type 2 DiabetesRC2DK088389 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI ALTSHULER, DAVID, BOEHNKE, MICHAEL L · 2009 to 2010
$17.9MMULTIDISCIPLINARY RESEARCH TRAINING IN CARDIOLOGYT32HL007208 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI Patrick Thomas Ellinor, David E Sosnovik · 1985 to 2026
$16.1MMultiethnic Study of Type 2 Diabetes GenesU01DK085526 · NIDDK · BROAD INSTITUTE, INC. · PI ALTSHULER, DAVID, JABLONSKI, KATHLEEN ANN · 2009 to 2014
$15.7MIdentifying Genes for Type 2 Diabetes: FUSIONU01DK062370 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI BOEHNKE, MICHAEL L, SCOTT, LAURA J. · 2009 to 2021
$11.6MEinstein's Nathan Shock Center of Excellence in Basic Biology of AgingP30AG038072 · NIA · ALBERT EINSTEIN COLLEGE OF MEDICINE, INC · PI CUERVO, ANA MARIA · 2010 to 2024
$10.8MA Large-Scale Schizophrenia Association Study in SwedenR01MH077139 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SULLIVAN, PATRICK F · 2007 to 2018
$9.9MA GENETIC LINKAGE STUDY OF GTSR01NS040024 · NINDS · TOURETTE SYNDROME ASSOCIATION, INC · PI PAULS, DAVID L · 2000 to 2004
$9.5MBritish Heart Foundation FS/14/55/30806British Heart Foundation RG/13/13/30194CIHR MOP136936CIHR MOP77682CIHR MOP82810Medical Research Council G0601261Medical Research Council G0800509Medical Research Council G0801418Medical Research Council MC_UP_1102/20Medical Research Council MR/L003120/1NHGRI NIH HHS 5U54HG003067-11NHGRI NIH HHS 5 U54 HG003067-13NHGRI NIH HHS U41 HG000330NHGRI NIH HHS U54HG003067NHLBI NIH HHS HHSN268201300046CNHLBI NIH HHS HHSN268201300047CNHLBI NIH HHS HHSN268201300048CNHLBI NIH HHS HHSN268201300049CNHLBI NIH HHS HHSN268201300050CNHLBI NIH HHS K01 HL125751NHLBI NIH HHS K01HL125751NHLBI NIH HHS R01HL107816NHLBI NIH HHS R01HL24799NHLBI NIH HHS T32 HL007208NIA NIH HHS P30 AG038072NIDDK NIH HHS 1RC2DK088389NIDDK NIH HHS DK085545NIDDK NIH HHS DK088389NIDDK NIH HHS DK098032NIDDK NIH HHS P30 DK020572NIDDK NIH HHS P30 DK043351NIDDK NIH HHS R01DK062370NIDDK NIH HHS R01 DK098032NIDDK NIH HHS R01DK098032NIDDK NIH HHS RC2-DK088389NIDDK NIH HHS RC2DK088389NIDDK NIH HHS RC2F DK088389NIDDK NIH HHS U01 DK062370NIDDK NIH HHS U01 DK085501NIDDK NIH HHS U01 DK085524NIDDK NIH HHS U01 DK085526NIDDK NIH HHS U01DK085526NIDDK NIH HHS U01 DK085545NIDDK NIH HHS U01-DK085545NIDDK NIH HHS U01 DK085584NIDDK NIH HHS U54 DK105566NIGMS NIH HHS F32GM115208NIGMS NIH HHS R01 GM104371NIMH NIH HHS 2P50MH066392-05A1NIMH NIH HHS MH077139NIMH NIH HHS MH089905NIMH NIH HHS MH094421NIMH NIH HHS MH095034NIMH NIH HHS R01 MH077139NIMH NIH HHS R01MH085521NIMH NIH HHS R01MH085560NIMH NIH HHS U01 MH094432NINDS NIH HHS K02 NS085048NINDS NIH HHS NS085048NINDS NIH HHS NS40024-09S1NINDS NIH HHS U01 NS040024NINDS NIH HHS U01 NS40024-09S1PHS HHS NIMHRC2MH089905Wellcome Trust 090367Wellcome Trust 090532Wellcome Trust 098381
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.
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Datasets as TopicDNA Mutational AnalysisExomeGenetic VariationHumansPhenotypeProteomeRare DiseasesSample SizeProteome
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