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; Daniel G MacArthur; Exome Aggregation Consortium

doi:10.1038/nature19057

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

Journal article

Open access

Peer reviewed

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, …

Nature (London), Vol.536(7616), pp.285-291

18/08/2016

DOI: https://doi.org/10.1038/nature19057

PMID: 27535533

Abstract

Datasets as Topic

DNA Mutational Analysis

Exome - genetics

Genetic Variation - genetics

Humans

Phenotype

Proteome - genetics

Rare Diseases - genetics

Sample Size

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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Title: Analysis of protein-coding genetic variation in 60,706 humans
Creators - without role: Monkol Lek - Massachusetts General Hospital
Konrad J Karczewski - Broad Institute
Eric V Minikel - Broad Institute
Kaitlin E Samocha - Massachusetts General Hospital
Eric Banks - Broad Institute
Timothy Fennell - Broad Institute
Anne H O'Donnell-Luria - Boston Children's Hospital
James S Ware - Imperial College London
Andrew J Hill - Massachusetts General Hospital
Beryl B Cummings - Broad Institute
Taru Tukiainen - Broad Institute
Daniel P Birnbaum - Broad Institute
Jack A Kosmicki - Massachusetts General Hospital
Laramie E Duncan - Massachusetts General Hospital
Karol Estrada - Massachusetts General Hospital
Fengmei Zhao - Massachusetts General Hospital
James Zou - Broad Institute
Emma Pierce-Hoffman - Massachusetts General Hospital
Joanne Berghout - Jackson Laboratory
David N Cooper - Cardiff University
Nicole Deflaux - Google
Mark DePristo - Broad Institute
Ron Do - Icahn School of Medicine at Mount Sinai
Jason Flannick - Broad Institute
Menachem Fromer - Massachusetts General Hospital
Laura Gauthier - Broad Institute
Jackie Goldstein - Massachusetts General Hospital
Namrata Gupta - Broad Institute
Daniel Howrigan - Massachusetts General Hospital
Adam Kiezun - Broad Institute
Mitja I Kurki - Broad Institute
Ami Levy Moonshine - Broad Institute
Pradeep Natarajan - Broad Institute
Lorena Orozco - National Institute of Genomic Medicine
Gina M Peloso - Center for Human Genetics
Ryan Poplin - Broad Institute
Manuel A Rivas - Broad Institute
Valentin Ruano-Rubio - Broad Institute
Samuel A Rose - Broad Institute
Douglas M Ruderfer - Icahn School of Medicine at Mount Sinai
Khalid Shakir - Broad Institute
Peter D Stenson - Cardiff University
Christine Stevens - Broad Institute
Brett P Thomas - Massachusetts General Hospital
Grace Tiao - Broad Institute
Maria T Tusie-Luna - Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
Ben Weisburd - Broad Institute
Hong-Hee Won - Samsung Medical Center
Dongmei Yu - Broad Institute
David M Altshuler - Broad Institute
Diego Ardissino - University of Parma
Michael Boehnke - University of Michigan–Ann Arbor
John Danesh - Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
Stacey Donnelly - Broad Institute
Roberto Elosua - Hospital Del Mar
Jose C Florez - Massachusetts General Hospital
Stacey B Gabriel - Broad Institute
Gad Getz - Broad Institute
Stephen J Glatt - SUNY Upstate Medical University
Christina M Hultman - Karolinska Institutet
Sekar Kathiresan - Broad Institute
Markku Laakso - Kuopio University Hospital
Steven McCarroll - Broad Institute
Mark I McCarthy - University of Oxford
Dermot McGovern - Cedars-Sinai Medical Center
Ruth McPherson - University of Ottawa
Benjamin M Neale - Massachusetts General Hospital
Aarno Palotie - Institute for Molecular Medicine Finland
Shaun M Purcell - Icahn School of Medicine at Mount Sinai
Danish Saleheen - University of Pennsylvania
Jeremiah M Scharf - Broad Institute
Pamela Sklar - Icahn School of Medicine at Mount Sinai
Patrick F Sullivan - University of North Carolina at Chapel Hill
Jaakko Tuomilehto - University of Helsinki
Ming T Tsuang - University of California, San Diego
Hugh C Watkins - University of Oxford
James G Wilson - University of Mississippi Medical Center
Mark J Daly - Broad Institute
Daniel G MacArthur - Massachusetts General Hospital
Exome Aggregation Consortium
Publication Details: Nature (London), Vol.536(7616), pp.285-291
Grant note: HHSN268201300048C / NHLBI NIH HHS U54HG003067 / NHGRI NIH HHS RC2DK088389 / NIDDK NIH HHS U01 NS40024-09S1 / NINDS NIH HHS U01 DK085545 / NIDDK NIH HHS 090532 / Wellcome Trust MH089905 / NIMH NIH HHS 090367 / Wellcome Trust G0800509 / Medical Research Council T32 HL007208 / NHLBI NIH HHS F32GM115208 / NIGMS NIH HHS MH077139 / NIMH NIH HHS R01DK098032 / NIDDK NIH HHS G0601261 / Medical Research Council U01 DK085526 / NIDDK NIH HHS R01HL107816 / NHLBI NIH HHS K01 HL125751 / NHLBI NIH HHS R01MH085560 / NIMH NIH HHS DK088389 / NIDDK NIH HHS MOP82810 / CIHR HHSN268201300049C / NHLBI NIH HHS U01 NS040024 / NINDS NIH HHS R01HL24799 / NHLBI NIH HHS NS085048 / NINDS NIH HHS G0801418 / Medical Research Council 2P50MH066392-05A1 / NIMH NIH HHS U01DK085526 / NIDDK NIH HHS MOP136936 / CIHR MC_UP_1102/20 / Medical Research Council U01 DK085524 / NIDDK NIH HHS MH095034 / NIMH NIH HHS R01 MH077139 / NIMH NIH HHS U01-DK085545 / NIDDK NIH HHS 5U54HG003067-11 / NHGRI NIH HHS U41 HG000330 / NHGRI NIH HHS R01MH085521 / NIMH NIH HHS R01 GM104371 / NIGMS NIH HHS MOP77682 / CIHR HHSN268201300047C / NHLBI NIH HHS NIMHRC2MH089905 / PHS HHS R01 DK098032 / NIDDK NIH HHS DK085545 / NIDDK NIH HHS P30 AG038072 / NIA NIH HHS RC2F DK088389 / NIDDK NIH HHS 5 U54 HG003067-13 / NHGRI NIH HHS MH094421 / NIMH NIH HHS HHSN268201300046C / NHLBI NIH HHS U01 DK085584 / NIDDK NIH HHS NS40024-09S1 / NINDS NIH HHS K01HL125751 / NHLBI NIH HHS RG/13/13/30194 / British Heart Foundation R01DK062370 / NIDDK NIH HHS MR/L003120/1 / Medical Research Council U01 DK085501 / NIDDK NIH HHS U01 DK062370 / NIDDK NIH HHS P30 DK020572 / NIDDK NIH HHS K02 NS085048 / NINDS NIH HHS 098381 / Wellcome Trust DK098032 / NIDDK NIH HHS U54 DK105566 / NIDDK NIH HHS U01 MH094432 / NIMH NIH HHS HHSN268201300050C / NHLBI NIH HHS P30 DK043351 / NIDDK NIH HHS RC2-DK088389 / NIDDK NIH HHS FS/14/55/30806 / British Heart Foundation 1RC2DK088389 / NIDDK NIH HHS
Identifiers: 9934317208331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article