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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, Eleina M. England, 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
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  • ORCID record for Konrad J. Karczewski
  • For correspondence: konradk@broadinstitute.org
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
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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
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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
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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
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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
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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
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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
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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
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Daniel P. Birnbaum
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
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Laura D. Gauthier
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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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
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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
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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
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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
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Moriel Singer-Berk
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
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Eleina M. England
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
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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
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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
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Raymond K. Walters
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
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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
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Yossi Farjoun
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Eric Banks
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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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
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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
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Cotton Seed
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
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Nicola Whiffin
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
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
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Jessica X. Chong
12Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA
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Kaitlin E. Samocha
13Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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Emma Pierce-Hoffman
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
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Zachary Zappala
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
14Vertex Pharmaceuticals Inc. Boston, MA, 02210
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Anne H. O’Donnell-Luria
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
15Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA
16Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
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Eric Vallabh Minikel
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Ben Weisburd
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Monkol Lek
17Department of Genetics, Yale School of Medicine, New Haven, Connecticut
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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
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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
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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
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Louis Bergelson
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Kristian Cibulskis
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Kristen M. Connolly
19Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Miguel Covarrubias
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Stacey Donnelly
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Steven Ferriera
20Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Stacey Gabriel
20Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Jeff Gentry
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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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
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Thibault Jeandet
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Diane Kaplan
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Christopher Llanwarne
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Ruchi Munshi
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Sam Novod
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Nikelle Petrillo
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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David Roazen
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Valentin Ruano-Rubio
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Andrea Saltzman
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Molly Schleicher
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Jose Soto
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Kathleen Tibbetts
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Charlotte Tolonen
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Gordon Wade
7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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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
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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
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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
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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
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Article Information

doi 
https://doi.org/10.1101/531210
History 
  • August 13, 2019.

Article Versions

  • Version 1 (January 28, 2019 - 13:55).
  • Version 2 (January 30, 2019 - 17:27).
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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 4.0 International license.

Author Information

  1. Konrad J. Karczewski1,2,*,
  2. Laurent C. Francioli1,2,
  3. Grace Tiao1,2,
  4. Beryl B. Cummings1,2,3,
  5. Jessica Alföldi1,2,
  6. Qingbo Wang1,2,4,
  7. Ryan L. Collins1,4,5,
  8. Kristen M. Laricchia1,2,
  9. Andrea Ganna1,2,6,
  10. Daniel P. Birnbaum1,2,
  11. Laura D. Gauthier7,
  12. Harrison Brand1,5,
  13. Matthew Solomonson1,2,
  14. Nicholas A. Watts1,2,
  15. Daniel Rhodes8,
  16. Moriel Singer-Berk1,2,
  17. Eleina M. England1,2,
  18. Eleanor G. Seaby1,2,
  19. Jack A. Kosmicki1,2,4,
  20. Raymond K. Walters1,2,9,
  21. Katherine Tashman1,2,9,
  22. Yossi Farjoun7,
  23. Eric Banks7,
  24. Timothy Poterba1,2,9,
  25. Arcturus Wang1,2,9,
  26. Cotton Seed1,2,9,
  27. Nicola Whiffin1,2,10,11,
  28. Jessica X. Chong12,
  29. Kaitlin E. Samocha13,
  30. Emma Pierce-Hoffman1,2,
  31. Zachary Zappala1,2,14,
  32. Anne H. O’Donnell-Luria1,2,15,16,
  33. Eric Vallabh Minikel1,
  34. Ben Weisburd7,
  35. Monkol Lek17,
  36. James S. Ware1,10,11,
  37. Christopher Vittal2,9,
  38. Irina M. Armean1,2,18,
  39. Louis Bergelson7,
  40. Kristian Cibulskis7,
  41. Kristen M. Connolly19,
  42. Miguel Covarrubias7,
  43. Stacey Donnelly1,
  44. Steven Ferriera20,
  45. Stacey Gabriel20,
  46. Jeff Gentry7,
  47. Namrata Gupta1,20,
  48. Thibault Jeandet7,
  49. Diane Kaplan7,
  50. Christopher Llanwarne7,
  51. Ruchi Munshi7,
  52. Sam Novod7,
  53. Nikelle Petrillo7,
  54. David Roazen7,
  55. Valentin Ruano-Rubio7,
  56. Andrea Saltzman1,
  57. Molly Schleicher1,
  58. Jose Soto7,
  59. Kathleen Tibbetts7,
  60. Charlotte Tolonen7,
  61. Gordon Wade7,
  62. Michael E. Talkowski1,5,21,
  63. The Genome Aggregation Database Consortium,
  64. Benjamin M. Neale1,2,9,
  65. Mark J. Daly1,2,6,9 and
  66. Daniel G. MacArthur1,2
  1. ↵*Corresponding author; email: konradk{at}broadinstitute.org
    1. 1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    2. 2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    3. 3Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA
    4. 4Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
    5. 5Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
    6. 6Institute for Molecular Medicine Finland, Helsinki, Finland
    7. 7Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    8. 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
    9. 9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    10. 10National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
    11. 11Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London, UK
    12. 12Department of Pediatrics, University of Washington, Seattle, Washington, 98195, USA
    13. 13Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
    14. 14Vertex Pharmaceuticals Inc. Boston, MA, 02210
    15. 15Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA
    16. 16Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
    17. 17Department of Genetics, Yale School of Medicine, New Haven, Connecticut
    18. 18European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
    19. 19Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    20. 20Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    21. 21Department of Neurology, Harvard Medical School, Boston, MA, USA
    22. 1Unidad de Investigacion de Enfermedades Metabolicas. Instituto Nacional de Ciencias Medicas y Nutricion. Mexico City
    23. 2Peninsula College of Medicine and Dentistry, Exeter, UK
    24. 3Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
    25. 4Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    26. 5Department of Cardiology, University Hospital, 43100 Parma, Italy
    27. 6Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
    28. 7Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA, 10461
    29. 8Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44122, USA
    30. 9Sorbonne Université, APHP, Gastroenterology Department, Saint Antoine Hospital, Paris, France
    31. 10NHLBI and Boston University’s Framingham Heart Study, Framingham, Massachusetts, USA
    32. 11Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
    33. 12Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA
    34. 13Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109
    35. 14National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
    36. 15The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
    37. 16Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
    38. 17Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
    39. 18Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
    40. 19Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
    41. 20NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
    42. 21Department of Epidemiology and Biostatistics, Imperial College London, London, UK
    43. 22Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK
    44. 23Imperial College Healthcare NHS Trust, Imperial College London, London, UK
    45. 24Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
    46. 25Department of Medicine, Harvard Medical School, Boston, MA
    47. 26Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
    48. 27McLean Hospital, Belmont, MA
    49. 28Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
    50. 29Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
    51. 30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
    52. 31Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    53. 32Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
    54. 33Department of Medicine and Pharmacology, University of Illinois at Chicago
    55. 34Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
    56. 35Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
    57. 36National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
    58. 37Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
    59. 38Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute (IMIM). Barcelona, Catalonia, Spain
    60. 39CIBER CV, Barcelona, Catalonia, Spain
    61. 40Departament of Medicine, Medical School, University of Vic-Central University of Catalonia. Vic, Catalonia, Spain
    62. 41Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
    63. 421. DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany
    64. 43University Heart Center Lübeck, 23562 Lübeck, Germany
    65. 44Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
    66. 45Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland
    67. 46Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital; Programs in Metabolism and Medical & Population Genetics, Broad Institute; Department of Medicine, Harvard Medical School
    68. 47Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany
    69. 48Bioinformatics Program, MGH Cancer Center and Department of Pathology
    70. 49Cancer Genome Computational Analysis, Broad Institute
    71. 50Endocrinology and Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
    72. 51Department of Psychiatry and Behavioral Sciences; SUNY Upstate Medical University
    73. 52Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, 1408, 701 West 168th Street, New York, New York 10032, USA
    74. 53Department of Genetics & Development, Columbia University Medical Center, Hammer Health Sciences, 1602, 701 West 168th Street, New York, New York 10032, USA
    75. 54Centro de Investigacion en Salud Poblacional. Instituto Nacional de Salud Publica MEXICO
    76. 55Lund University, Sweden
    77. 56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
    78. 57Lund University Diabetes Centre
    79. 58Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030
    80. 59Department of Neurology, Columbia University
    81. 60Institute of Genomic Medicine, Columbia University
    82. 61Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
    83. 62Department of Psychiatry, PL 320, Helsinki University Central Hospital, Lapinlahdentie, 00 180 Helsinki, Finland
    84. 63Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
    85. 64Icahn School of Medicine at Mount Sinai, New York, NY, USA
    86. 65Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
    87. 66Department of Public Health, Faculty of Medicine, University of Helsinki, Finland
    88. 67Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
    89. 68Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
    90. 69Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea
    91. 70MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ
    92. 71National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK
    93. 72Department of Health, THL-National Institute for Health and Welfare, 00271 Helsinki, Finland
    94. 73Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut3Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut
    95. 74Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
    96. 75Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
    97. 76The University of Eastern Finland, Institute of Clinical Medicine, Kuopio, Finland
    98. 77Kuopio University Hospital, Kuopio, Finland
    99. 78Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Finland
    100. 79The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
    101. 80Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
    102. 81Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China
    103. 82Cardiovascular Research REGICOR Group, Hospital del Mar Medical Research Institute (IMIM). Barcelona, Catalonia
    104. 83Department of Genetics, Harvard Medical School, Boston, MA, USA
    105. 84Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ UK
    106. 85Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
    107. 86Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
    108. 87F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
    109. 88Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada
    110. 89Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114
    111. 90Program in Population and Medical Genetics, Broad Institute, Cambridge, MA
    112. 91Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden
    113. 92Lund University, Dept. Clinical Sciences, Skane University Hospital, Malmo, Sweden
    114. 93Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, 14610, Mexico
    115. 94Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
    116. 95Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
    117. 96Department of Psychiatry, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA
    118. 97Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    119. 98Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG
    120. 99Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland
    121. 100Research Center, Montreal Heart Institute, Montreal, Quebec, Canada, H1T 1C8
    122. 101Department of Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
    123. 102Broad Institute of MIT and Harvard, Cambridge MA, USA
    124. 103Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    125. 104Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
    126. 105Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
    127. 106Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
    128. 107Center for Non-Communicable Diseases, Karachi, Pakistan
    129. 108National Institute for Health and Welfare, Helsinki, Finland
    130. 109Deutsches Herzzentrum München, Germany
    131. 110Technische Universität München
    132. 111Division of Cardiovascular Medicine, Nashville VA Medical Center and Vanderbilt University, School of Medicine, Nashville, TN 37232-8802, USA
    133. 112Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    134. 113Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    135. 114Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
    136. 115Institute of Clinical Medicine, neurology, University of Eastern Finad, Kuopio, Finland
    137. 116Department of Twin Research and Genetic Epidemiology, King’s College London, London UK
    138. 117Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA
    139. 118Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore
    140. 119Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
    141. 120Duke-NUS Graduate Medical School, Singapore
    142. 121Life Sciences Institute, National University of Singapore, Singapore
    143. 122Department of Statistics and Applied Probability, National University of Singapore, Singapore
    144. 123Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
    145. 124HUCH Abdominal Center, Helsinki University Hospital, Helsinki, Finland
    146. 125Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego
    147. 126Institute of Genomic Medicine, University of California, San Diego
    148. 127Juliet Keidan Institute of Pediatric Gastroenterology, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
    149. 128Instituto de Investigaciones Biomédicas UNAM Mexico City
    150. 129Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán Mexico City
    151. 130National Heart & Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, London UK
    152. 131Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
    153. 132Radcliffe Department of Medicine, University of Oxford, Oxford UK
    154. 133Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
    155. 134Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
    156. 135Program in Infectious Disease and Microbiome, Broad Institute of MIT and Harvard, Cambridge, MA, USA
    157. 136Center for Computational and Integrative Biology, Massachusetts General Hospital
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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
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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
    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, Eleina M. England, 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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    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, Eleina M. England, 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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