New Results
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, 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 Duncan, Karol Estrada, Fengmei Zhao, James Zou, Emma Pierce-Hoffman, David N Cooper, 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, 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, Roberto Elosua, Jose C Florez, Stacey B Gabriel, Gad Getz, 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 Scharf, Pamela Sklar, Patrick F Sullivan, Jaakko Tuomilehto, Hugh C Watkins, James G Wilson, Mark J Daly, Daniel G MacArthur
doi: https://doi.org/10.1101/030338
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Monkol Lek
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
3School of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia
4Institute for Neuroscience and Muscle Research, Childrens Hospital at Westmead, Sydney, NSW, Australia
Konrad J Karczewski
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Eric V Minikel
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
Kaitlin E Samocha
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
Eric Banks
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Timothy Fennell
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Anne H O’Donnell-Luria
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
7Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA
James S Ware
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
8Department of Genetics, Harvard Medical School, Boston, MA, USA
9National Heart and Lung Institute, Imperial College London, London, UK
10NIHR Royal Brompton Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK
11MRC Clinical Sciences Centre, Imperial College London, London, UK
Andrew J Hill
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
12Genome Sciences, University of Washington, Seattle, WA, USA
Beryl B Cummings
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
5Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, USA
Taru Tukiainen
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Daniel P Birnbaum
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jack A Kosmicki
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
13Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA, USA
Laramie Duncan
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Karol Estrada
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Fengmei Zhao
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
James Zou
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Emma Pierce-Hoffman
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
David N Cooper
14Institute of Medical Genetics, Cardiff University, Cardiff, UK
Mark DePristo
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Ron Do
16Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
17Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
18The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
19The Center for Statistical Genetics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Jason Flannick
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
20Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA
Menachem Fromer
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
21Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
16Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
17Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Laura Gauthier
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Jackie Goldstein
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Namrata Gupta
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Daniel Howrigan
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Adam Kiezun
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Mitja I Kurki
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
22Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
Ami Levy Moonshine
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Pradeep Natarajan
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
23Harvard Medical School, Boston, MA, USA
24Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
25Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
Lorena Orozco
26Immunogenomics and Metabolic Disease Laboratory, Instituto Nacional de Medicina Genomica, Mexico City, Mexico
Gina M Peloso
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
24Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
25Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
Ryan Poplin
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Manuel A Rivas
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Valentin Ruano-Rubio
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Douglas M Ruderfer
21Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
16Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
17Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Khalid Shakir
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Peter D Stenson
14Institute of Medical Genetics, Cardiff University, Cardiff, UK
Christine Stevens
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Brett P Thomas
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Grace Tiao
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
Maria T Tusie-Luna
27Department of Endocrinology and Metabolism, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico
Ben Weisburd
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Hong-Hee Won
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
23Harvard Medical School, Boston, MA, USA
24Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
25Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
Dongmei Yu
22Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
28Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
David M Altshuler
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
29Vertex Pharmaceuticals, Boston, MA, USA
Diego Ardissino
30Department of Cardiology, University Hospital, Parma, Italy
Michael Boehnke
31Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
John Danesh
32Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK
Roberto Elosua
33Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute, Barcelona, Spain
Jose C Florez
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
23Harvard Medical School, Boston, MA, USA
24Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
Stacey B Gabriel
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Gad Getz
15Broad Institute of MIT and Harvard, Cambridge, MA, USA
23Harvard Medical School, Boston, MA, USA
34Department of Pathology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA
Christina M Hultman
35Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
Sekar Kathiresan
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
23Harvard Medical School, Boston, MA, USA
24Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA
25Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
Markku Laakso
36Department of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland
Steven McCarroll
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
8Department of Genetics, Harvard Medical School, Boston, MA, USA
Mark I McCarthy
37Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
38Oxford Centre for Diabetes,Endocrinology and Metabolism, University of Oxford, Oxford, UK
39Oxford NIHR Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
Dermot McGovern
40Inflammatory Bowel Disease and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Ruth McPherson
41Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON, Canada
Benjamin M Neale
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Aarno Palotie
42Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland
Shaun M Purcell
21Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
16Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
17Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Danish Saleheen
43Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
44Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
45Center for Non-Communicable Diseases, Karachi, Pakistan
Jeremiah Scharf
22Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
28Department of Neurology, Brigham and Women’s Hospital, Boston, MA, USA
Pamela Sklar
21Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
16Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
17Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
46Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
47Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Patrick F Sullivan
48Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
49Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Jaakko Tuomilehto
50Department of Public Health, University of Helsinki, Helsinki, Finland
Hugh C Watkins
51Radcliffe Department of Medicine, University of Oxford, Oxford, UK
James G Wilson
52Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA
Mark J Daly
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
6Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Daniel G MacArthur
1Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
2Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
Summary
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) sequence data for 60,706 individuals of diverse ethnicities. The resulting catalogue of human genetic diversity has unprecedented resolution, with an average of one variant every eight bases of coding sequence and the presence of widespread mutational recurrence. The deep catalogue of variation provided by the Exome Aggregation Consortium (ExAC) can be used to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; we identify 3,230 genes with near-complete depletion of truncating variants, 79% of which have no currently established human disease phenotype. Finally, we show 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.
Footnotes
↵# List of collaborators to appear in Supplementary
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
Posted October 30, 2015.
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, 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 Duncan, Karol Estrada, Fengmei Zhao, James Zou, Emma Pierce-Hoffman, David N Cooper, 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, 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, Roberto Elosua, Jose C Florez, Stacey B Gabriel, Gad Getz, 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 Scharf, Pamela Sklar, Patrick F Sullivan, Jaakko Tuomilehto, Hugh C Watkins, James G Wilson, Mark J Daly, Daniel G MacArthur
bioRxiv 030338; doi: https://doi.org/10.1101/030338
Analysis of protein-coding genetic variation in 60,706 humans
Exome Aggregation Consortium, 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 Duncan, Karol Estrada, Fengmei Zhao, James Zou, Emma Pierce-Hoffman, David N Cooper, 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, 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, Roberto Elosua, Jose C Florez, Stacey B Gabriel, Gad Getz, 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 Scharf, Pamela Sklar, Patrick F Sullivan, Jaakko Tuomilehto, Hugh C Watkins, James G Wilson, Mark J Daly, Daniel G MacArthur
bioRxiv 030338; doi: https://doi.org/10.1101/030338
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