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Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes
View ORCID ProfileKonrad J. Karczewski, Laurent C. Francioli, Grace Tiao, Beryl B. Cummings, Jessica Alföldi, Qingbo Wang, Ryan L. Collins, Kristen M. Laricchia, Andrea Ganna, Daniel P. Birnbaum, Laura D. Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A. Watts, Daniel Rhodes, Moriel Singer-Berk, Eleanor G. Seaby, Jack A. Kosmicki, Raymond K. Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X. Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O’Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S. Ware, Christopher Vittal, Irina M. Armean, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, The Genome Aggregation Database Consortium, Benjamin M. Neale, Mark J. Daly, Daniel G. MacArthur
doi: https://doi.org/10.1101/531210
Konrad J. Karczewski
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Laurent C. Francioli
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Grace Tiao
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Beryl B. Cummings
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
Jessica Alföldi
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Qingbo Wang
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
4Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
Ryan L. Collins
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
4Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Kristen M. Laricchia
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Andrea Ganna
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
6Institute for Molecular Medicine Finland, Helsinki, Finland
Daniel P. Birnbaum
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Laura D. Gauthier
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Harrison Brand
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
Matthew Solomonson
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Nicholas A. Watts
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Daniel Rhodes
8Centre for Translational Bioinformatics, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, UK
Moriel Singer-Berk
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Eleanor G. Seaby
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Jack A. Kosmicki
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
4Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
Raymond K. Walters
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Katherine Tashman
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Yossi Farjoun
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Eric Banks
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Timothy Poterba
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Arcturus Wang
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Cotton Seed
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Nicola Whiffin
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
10National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London UK
11Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
Jessica X. Chong
12Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA
Kaitlin E. Samocha
13Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
Emma Pierce-Hoffman
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Zachary Zappala
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
14Vertex Pharmaceuticals Inc. Boston, MA, 02210
Anne H. O’Donnell-Luria
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
15Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA
16Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
Eric Vallabh Minikel
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Ben Weisburd
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Monkol Lek
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
17Department of Genetics, Yale School of Medicine, New Haven, Connecticut
James S. Ware
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
10National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London UK
11Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
Christopher Vittal
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Irina M. Armean
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
18European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
Louis Bergelson
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Kristian Cibulskis
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Kristen M. Connolly
19Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Miguel Covarrubias
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Stacey Donnelly
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Steven Ferriera
20Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Stacey Gabriel
20Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Jeff Gentry
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Namrata Gupta
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
20Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Thibault Jeandet
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Diane Kaplan
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Christopher Llanwarne
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Ruchi Munshi
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Sam Novod
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Nikelle Petrillo
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
David Roazen
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Valentin Ruano-Rubio
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Andrea Saltzman
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Molly Schleicher
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Jose Soto
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Kathleen Tibbetts
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Charlotte Tolonen
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Gordon Wade
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Michael E. Talkowski
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
21Department of Neurology, Harvard Medical School, Boston, MA, USA
Benjamin M. Neale
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Mark J. Daly
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
6Institute for Molecular Medicine Finland, Helsinki, Finland
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
Daniel G. MacArthur
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
Posted January 30, 2019.
Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes
Konrad J. Karczewski, Laurent C. Francioli, Grace Tiao, Beryl B. Cummings, Jessica Alföldi, Qingbo Wang, Ryan L. Collins, Kristen M. Laricchia, Andrea Ganna, Daniel P. Birnbaum, Laura D. Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A. Watts, Daniel Rhodes, Moriel Singer-Berk, Eleanor G. Seaby, Jack A. Kosmicki, Raymond K. Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X. Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O’Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S. Ware, Christopher Vittal, Irina M. Armean, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, The Genome Aggregation Database Consortium, Benjamin M. Neale, Mark J. Daly, Daniel G. MacArthur
bioRxiv 531210; doi: https://doi.org/10.1101/531210
Variation across 141,456 human exomes and genomes reveals the spectrum of loss-of-function intolerance across human protein-coding genes
Konrad J. Karczewski, Laurent C. Francioli, Grace Tiao, Beryl B. Cummings, Jessica Alföldi, Qingbo Wang, Ryan L. Collins, Kristen M. Laricchia, Andrea Ganna, Daniel P. Birnbaum, Laura D. Gauthier, Harrison Brand, Matthew Solomonson, Nicholas A. Watts, Daniel Rhodes, Moriel Singer-Berk, Eleanor G. Seaby, Jack A. Kosmicki, Raymond K. Walters, Katherine Tashman, Yossi Farjoun, Eric Banks, Timothy Poterba, Arcturus Wang, Cotton Seed, Nicola Whiffin, Jessica X. Chong, Kaitlin E. Samocha, Emma Pierce-Hoffman, Zachary Zappala, Anne H. O’Donnell-Luria, Eric Vallabh Minikel, Ben Weisburd, Monkol Lek, James S. Ware, Christopher Vittal, Irina M. Armean, Louis Bergelson, Kristian Cibulskis, Kristen M. Connolly, Miguel Covarrubias, Stacey Donnelly, Steven Ferriera, Stacey Gabriel, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Christopher Llanwarne, Ruchi Munshi, Sam Novod, Nikelle Petrillo, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Molly Schleicher, Jose Soto, Kathleen Tibbetts, Charlotte Tolonen, Gordon Wade, Michael E. Talkowski, The Genome Aggregation Database Consortium, Benjamin M. Neale, Mark J. Daly, Daniel G. MacArthur
bioRxiv 531210; doi: https://doi.org/10.1101/531210
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