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Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals

View ORCID ProfileNicola Whiffin, View ORCID ProfileKonrad J Karczewski, Xiaolei Zhang, Sonia Chothani, View ORCID ProfileMiriam J Smith, View ORCID ProfileD Gareth Evans, View ORCID ProfileAngharad M Roberts, Nicholas M Quaife, Sebastian Schafer, View ORCID ProfileOwen Rackham, Jessica Alföldi, Anne H O’Donnell-Luria, Laurent C Francioli, Genome Aggregation Database (gnomAD) Production Team, Jessica Alföldi, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Ryan L Collins, Kristen M. Connolly, Miguel Covarrubias, Beryl Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Laurent Francioli, Stacey Gabriel, Laura D. Gauthier, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Konrad J. Karczewski, Kristen M. Laricchia, Christopher Llanwarne, Eric V. Minikel, Ruchi Munshi, Benjamin M Neale, Sam Novod, View ORCID ProfileAnne H. O’Donnell-Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, Matthew Solomonson, Jose Soto, Grace Tiao, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, View ORCID ProfileJames S Ware, Nicholas A Watts, Ben Weisburd, Nicola Whiffin, Genome Aggregation Database (gnomAD) Consortium, Carlos A Aguilar Salinas, Tariq Ahmad, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W Bowden, Matthew J Bown, John C Chambers, Juliana C. Chan, Daniel Chasman, Judy Cho, Mina K. Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Mark J. Daly, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J.F. Loos, Steven A. Lubitz, Ronald C.W. Ma, Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven McCarroll, Mark I McCarthy, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Benjamin M Neale, Peter M Nilsson, Michael C O’Donovan, Dost Ongur, Lorena Orozco, Michael J Owen, Colin N.A. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E. Pulver, Nazneen Rahman, Anne M. Remes, John D. Rioux, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Jeremiah Scharf, Heribert Schunkert, Moore B. Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Soko, Tim Spector, Patrick F. Sullivan, Jaana Suvisaari, E Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, James S Ware, Hugh Watkins, Rinse K Weersma, Maija Wessman, James G. Wilson, Ramnik J. Xavier, Stuart A Cook, View ORCID ProfilePaul J R Barton, Daniel G MacArthur, View ORCID ProfileJames S Ware
doi: https://doi.org/10.1101/543504
Nicola Whiffin
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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  • ORCID record for Nicola Whiffin
  • For correspondence: n.whiffin@imperial.ac.uk
Konrad J Karczewski
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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  • ORCID record for Konrad J Karczewski
Xiaolei Zhang
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Sonia Chothani
6Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
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Miriam J Smith
5NW Genomic Laboratory Hub, Centre for Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, St Mary’s Hospital, Manchester, UK
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  • ORCID record for Miriam J Smith
D Gareth Evans
5NW Genomic Laboratory Hub, Centre for Genomic Medicine, Division of Evolution and Genomic Science, University of Manchester, St Mary’s Hospital, Manchester, UK
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  • ORCID record for D Gareth Evans
Angharad M Roberts
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Nicholas M Quaife
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Sebastian Schafer
6Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
7National Heart Centre Singapore, Singapore
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Owen Rackham
6Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
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  • ORCID record for Owen Rackham
Jessica Alföldi
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Anne H O’Donnell-Luria
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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Laurent C Francioli
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 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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Irina M. Armean
3European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD, United Kingdom
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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Eric Banks
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Louis Bergelson
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Kristian Cibulskis
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Ryan L Collins
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
6Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
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Kristen M. Connolly
7Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Miguel Covarrubias
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Beryl 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
8Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, 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
9Stanley Center for Psychiatric Research, 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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Yossi Farjoun
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Steven Ferriera
10Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Laurent 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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Stacey Gabriel
10Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Laura D. Gauthier
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Jeff Gentry
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Namrata Gupta
10Broad Genomics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Thibault Jeandet
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Diane Kaplan
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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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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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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Christopher Llanwarne
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Eric V. Minikel
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Ruchi Munshi
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, 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
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Sam Novod
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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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
11Division of Genetics and Genomics, Boston Children’s Hospital, Boston, Massachusetts 02115, USA
12Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
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Nikelle Petrillo
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Timothy Poterba
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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David Roazen
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Valentin Ruano-Rubio
4Data 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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Kaitlin E. Samocha
13Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
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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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Cotton Seed
9Stanley Center for Psychiatric Research, 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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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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Jose Soto
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, 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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Kathleen Tibbetts
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Charlotte Tolonen
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Christopher Vittal
9Stanley Center for Psychiatric Research, 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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Gordon Wade
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Arcturus Wang
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
2Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, 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
6Program in Bioinformatics and Integrative Genomics, Harvard Medical School, Boston, MA 02115, USA
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James S Ware
14National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London UK
15Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, 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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Ben Weisburd
4Data Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Nicola Whiffin
14National Heart & Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London UK
15Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
1Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Carlos A Aguilar Salinas
1Unidad de Investigacion de Enfermedades Metabolicas. Instituto Nacional de Ciencias Medicas y Nutricion. Mexico City
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Tariq Ahmad
2Peninsula College of Medicine and Dentistry, Exeter, UK
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Christine M. Albert
3Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
4Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Diego Ardissino
5Department of Cardiology, University Hospital, 43100 Parma, Italy
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Gil Atzmon
6Department of Biology, Faculty of Natural Sciences, University of Haifa, Haifa, Israel
7Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY, USA 10461
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John Barnard
8Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44122, USA
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Laurent Beaugerie
9Sorbonne Université, APHP, Gastroenterology Department, Saint Antoine Hospital, Paris, France
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Emelia J. Benjamin
10NHLBI and Boston University’s Framingham Heart Study, Framingham, Massachusetts, USA
11Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
12Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA
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Michael Boehnke
13Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109
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Lori L. Bonnycastle
14National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
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Erwin P. Bottinger
15The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
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Donald W Bowden
16Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA
17Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
18Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA
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Matthew J Bown
19Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
20NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
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John C Chambers
21Department of Epidemiology and Biostatistics, Imperial College London, London, UK
22Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK
23Imperial College Healthcare NHS Trust, Imperial College London, London, UK
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Juliana C. Chan
24Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
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Daniel Chasman
3Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA
25Department of Medicine, Harvard Medical School, Boston, MA
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Judy Cho
15Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
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Mina K. Chung
26Departments of Cardiovascular Medicine, Cellular and Molecular Medicine, Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio, USA
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Bruce Cohen
27McLean Hospital, Belmont, MA
25Department of Medicine, Harvard Medical School, Boston, MA
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Adolfo Correa
28Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
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Dana Dabelea
29Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA
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Mark J. Daly
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
31Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
32Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Dawood Darbar
33Department of Medicine and Pharmacology, University of Illinois at Chicago
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Ravindranath Duggirala
34Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX, USA
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Josée Dupuis
35Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA
36National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, MA 01702, USA
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Patrick T. Ellinor
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
37Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
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Roberto Elosua
38Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute (IMIM). Barcelona, Catalonia, Spain
39CIBER CV, Barcelona, Catalonia, Spain
40Departament of Medicine, Medical School, University of Vic-Central University of Catalonia. Vic, Catalonia, Spain
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Jeanette Erdmann
41Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
421. DZHK (German Research Centre for Cardiovascular Research), partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany
43University Heart Center Lübeck, 23562 Lübeck, Germany
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Tõnu Esko
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
44Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Martti Färkkilä
45Helsinki University and Helsinki University Hospital, Clinic of Gastroenterology, Helsinki, Finland
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Jose Florez
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
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Andre Franke
47Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel, Germany
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Gad Getz
48Bioinformatics Program, MGH Cancer Center and Department of Pathology
49Cancer Genome Computational Analysis, Broad Institute.
25Department of Medicine, Harvard Medical School, Boston, MA
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Benjamin Glaser
50Endocrinology and Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Stephen J. Glatt
51Department of Psychiatry and Behavioral Sciences; SUNY Upstate Medical University
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David Goldstein
52Institute for Genomic Medicine, Columbia University Medical Center, Hammer Health Sciences, 1408, 701 West 168th Street, New York, New York 10032, USA
53Department of Genetics & Development, Columbia University Medical Center, Hammer Health Sciences, 1602, 701 West 168th Street, New York, New York 10032, USA
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Clicerio Gonzalez
54Centro de Investigacion en Salud Poblacional. Instituto Nacional de Salud Publica MEXICO
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Leif Groop
55Lund University, Sweden
56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
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Christopher Haiman
57Lund University Diabetes Centre
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58Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030
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59Department of Neurology, Columbia University
60Institute of Genomic Medicine, Columbia University
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61Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
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62Department of Psychiatry, PL 320, Helsinki University Central Hospital, Lapinlahdentie, 00 180 Helsinki, Finland
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Christina M. Hultman
63Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
64Icahn School of Medicine at Mount Sinai, New York, NY, USA
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65Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland
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56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
66Department of Public Health, Faculty of Medicine, University of Helsinki, Finland
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Sekar Kathiresan
67Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
68Cardiovascular Disease Initiative and Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
25Department of Medicine, Harvard Medical School, Boston, MA
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69Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea
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69Center for Genome Science, Korea National Institute of Health, Chungcheongbuk-do, Republic of Korea
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70MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ
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Jaspal Kooner
23Imperial College Healthcare NHS Trust, Imperial College London, London, UK
22Department of Cardiology, Ealing Hospital NHS Trust, Southall, UK
71National Heart and Lung Institute, Cardiovascular Sciences, Hammersmith Campus, Imperial College London, London, UK
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72Department of Health, THL-National Institute for Health and Welfare, 00271 Helsinki, Finland
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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.
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74Division of Pediatric Gastroenterology, Emory University School of Medicine, Atlanta, Georgia, USA
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75Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
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76The University of Eastern Finland, Institute of Clinical Medicine, Kuopio, Finland
77Kuopio University Hospital, Kuopio, Finland
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78Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Finland
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Ruth J.F. Loos
15Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
79The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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Steven A. Lubitz
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
37Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA
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Ronald C.W. Ma
24Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
80Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
81Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China
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Daniel G. MacArthur
31Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Jaume Marrugat
82Cardiovascular Research REGICOR Group, Hospital del Mar Medical Research Institute (IMIM). Barcelona, Catalonia
39CIBER CV, Barcelona, Catalonia, Spain
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Kari M. Mattila
78Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere, Faculty of Medicine and Health Technology, Tampere University, Finland
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Steven McCarroll
32Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
83Department of Genetics, Harvard Medical School, Boston, MA, USA
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Mark I McCarthy
84Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LJ UK
85Wellcome Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
86Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK
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Dermot McGovern
87F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Ruth McPherson
88Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, Canada
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James B. Meigs
89Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114
25Department of Medicine, Harvard Medical School, Boston, MA
90Program in Population and Medical Genetics, Broad Institute, Cambridge, MA
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Olle Melander
91Department of Clinical Sciences, University Hospital Malmo Clinical Research Center, Lund University, Malmo, Sweden
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Andres Metspalu
44Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia
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Benjamin M Neale
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
31Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Peter M Nilsson
92Lund University, Dept. Clinical Sciences, Skane University Hospital, Malmo, Sweden
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Michael C O’Donovan
70MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ
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Dost Ongur
27McLean Hospital, Belmont, MA
25Department of Medicine, Harvard Medical School, Boston, MA
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Lorena Orozco
93Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, 14610, Mexico
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Michael J Owen
70MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff University School of Medicine, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ
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Colin N.A. Palmer
94Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
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Aarno Palotie
56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
32Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
31Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Kyong Soo Park
75Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
95Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
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Carlos Pato
96Department of Psychiatry, Keck School of Medicine at the University of Southern California, Los Angeles, California, USA
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Ann E. Pulver
97Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Nazneen Rahman
98Division of Genetics and Epidemiology, Institute of Cancer Research, London SM2 5NG
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Anne M. Remes
99Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology, University of Oulu, Oulu, Finland
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John D. Rioux
100Research Center, Montreal Heart Institute, Montreal, Quebec, Canada H1T 1C8
101Department of Medicine, Faculty of Medicine, Université de Montréal, Québec, Canada
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Samuli Ripatti
56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
66Department of Public Health, Faculty of Medicine, University of Helsinki, Finland
102Broad Institute of MIT and Harvard, Cambridge MA, USA
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Dan M. Roden
103Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
104Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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Danish Saleheen
105Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
106Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
107Center for Non-Communicable Diseases, Karachi, Pakistan
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Veikko Salomaa
108National Institute for Health and Welfare, Helsinki, Finland
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Nilesh J. Samani
19Department of Cardiovascular Sciences, University of Leicester, Leicester, UK
20NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK
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Jeremiah Scharf
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
32Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
67Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA
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Heribert Schunkert
109Deutsches Herzzentrum München, Germany
110Technische Universität München
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Moore B. Shoemaker
111Division of Cardiovascular Medicine, Nashville VA Medical Center and Vanderbilt University, School of Medicine, Nashville, TN 37232-8802, USA
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Pamela Sklar
112Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA
113Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
114Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Hilkka Soininen
115Institute of Clinical Medicine, neurology, University of Eastern Finad, Kuopio, Finland
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Harry Soko
9Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA
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Tim Spector
116Department of Twin Research and Genetic Epidemiology, King’s College London, London UK
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Patrick F. Sullivan
63Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
117Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA
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Jaana Suvisaari
108National Institute for Health and Welfare, Helsinki, Finland
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E Shyong Tai
118Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore
119Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
120Duke-NUS Graduate Medical School, Singapore
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Yik Ying Teo
118Saw Swee Hock School of Public Health, National University of Singapore, National University Health System, Singapore
121Life Sciences Institute, National University of Singapore, Singapore
122Department of Statistics and Applied Probability, National University of Singapore, Singapore
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Tuomi Tiinamaija
56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
123Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
124HUCH Abdominal Center, Helsinki University Hospital, Helsinki, Finland
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Ming Tsuang
125Center for Behavioral Genomics, Department of Psychiatry, University of California, San Diego
126Institute of Genomic Medicine, University of California, San Diego
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Dan Turner
127Juliet Keidan Institute of Pediatric Gastroenterology, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
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Teresa Tusie-Luna
128Instituto de Investigaciones Biomédicas, UNAM Mexico City
129Instituto Nacional de Ciencias Médicas, y Nutrición Salvador Zubirán Mexico City
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Erkki Vartiainen
66Department of Public Health, Faculty of Medicine, University of Helsinki, Finland
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James S Ware
130National Heart & Lung Institute & MRC London Institute of Medical Sciences, Imperial College London, London UK
131Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Trust, London UK
30Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Hugh Watkins
132Radcliffe Department of Medicine, University of Oxford, Oxford UK
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Rinse K Weersma
133Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands
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Maija Wessman
123Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland
56Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland
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James G. Wilson
134Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA
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Ramnik J. Xavier
135Program in Infectious Disease and Microbiome, Broad Institute of MIT and Harvard, Cambridge, MA, USA
136Center for Computational and Integrative Biology, Massachusetts General Hospital
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Stuart A Cook
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
6Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 8 College Road, Singapore
7National Heart Centre Singapore, Singapore
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Paul J R Barton
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
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Daniel G MacArthur
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
4Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA
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James S Ware
1National Heart and Lung Institute and MRC London Institute of Medical Sciences, Imperial College London, London, UK
2NIHR Royal Brompton Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
3Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
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Abstract

Upstream open reading frames (uORFs) are important tissue-specific cis-regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding loss-of-function variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.

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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.
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Posted February 07, 2019.
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Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals
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Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals
Nicola Whiffin, Konrad J Karczewski, Xiaolei Zhang, Sonia Chothani, Miriam J Smith, D Gareth Evans, Angharad M Roberts, Nicholas M Quaife, Sebastian Schafer, Owen Rackham, Jessica Alföldi, Anne H O’Donnell-Luria, Laurent C Francioli, Genome Aggregation Database (gnomAD) Production Team, Jessica Alföldi, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Ryan L Collins, Kristen M. Connolly, Miguel Covarrubias, Beryl Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Laurent Francioli, Stacey Gabriel, Laura D. Gauthier, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Konrad J. Karczewski, Kristen M. Laricchia, Christopher Llanwarne, Eric V. Minikel, Ruchi Munshi, Benjamin M Neale, Sam Novod, Anne H. O’Donnell-Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, Matthew Solomonson, Jose Soto, Grace Tiao, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, James S Ware, Nicholas A Watts, Ben Weisburd, Nicola Whiffin, Genome Aggregation Database (gnomAD) Consortium, Carlos A Aguilar Salinas, Tariq Ahmad, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W Bowden, Matthew J Bown, John C Chambers, Juliana C. Chan, Daniel Chasman, Judy Cho, Mina K. Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Mark J. Daly, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J.F. Loos, Steven A. Lubitz, Ronald C.W. Ma, Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven McCarroll, Mark I McCarthy, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Benjamin M Neale, Peter M Nilsson, Michael C O’Donovan, Dost Ongur, Lorena Orozco, Michael J Owen, Colin N.A. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E. Pulver, Nazneen Rahman, Anne M. Remes, John D. Rioux, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Jeremiah Scharf, Heribert Schunkert, Moore B. Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Soko, Tim Spector, Patrick F. Sullivan, Jaana Suvisaari, E Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, James S Ware, Hugh Watkins, Rinse K Weersma, Maija Wessman, James G. Wilson, Ramnik J. Xavier, Stuart A Cook, Paul J R Barton, Daniel G MacArthur, James S Ware
bioRxiv 543504; doi: https://doi.org/10.1101/543504
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Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals
Nicola Whiffin, Konrad J Karczewski, Xiaolei Zhang, Sonia Chothani, Miriam J Smith, D Gareth Evans, Angharad M Roberts, Nicholas M Quaife, Sebastian Schafer, Owen Rackham, Jessica Alföldi, Anne H O’Donnell-Luria, Laurent C Francioli, Genome Aggregation Database (gnomAD) Production Team, Jessica Alföldi, Irina M. Armean, Eric Banks, Louis Bergelson, Kristian Cibulskis, Ryan L Collins, Kristen M. Connolly, Miguel Covarrubias, Beryl Cummings, Mark J. Daly, Stacey Donnelly, Yossi Farjoun, Steven Ferriera, Laurent Francioli, Stacey Gabriel, Laura D. Gauthier, Jeff Gentry, Namrata Gupta, Thibault Jeandet, Diane Kaplan, Konrad J. Karczewski, Kristen M. Laricchia, Christopher Llanwarne, Eric V. Minikel, Ruchi Munshi, Benjamin M Neale, Sam Novod, Anne H. O’Donnell-Luria, Nikelle Petrillo, Timothy Poterba, David Roazen, Valentin Ruano-Rubio, Andrea Saltzman, Kaitlin E. Samocha, Molly Schleicher, Cotton Seed, Matthew Solomonson, Jose Soto, Grace Tiao, Kathleen Tibbetts, Charlotte Tolonen, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, James S Ware, Nicholas A Watts, Ben Weisburd, Nicola Whiffin, Genome Aggregation Database (gnomAD) Consortium, Carlos A Aguilar Salinas, Tariq Ahmad, Christine M. Albert, Diego Ardissino, Gil Atzmon, John Barnard, Laurent Beaugerie, Emelia J. Benjamin, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W Bowden, Matthew J Bown, John C Chambers, Juliana C. Chan, Daniel Chasman, Judy Cho, Mina K. Chung, Bruce Cohen, Adolfo Correa, Dana Dabelea, Mark J. Daly, Dawood Darbar, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, Jeanette Erdmann, Tõnu Esko, Martti Färkkilä, Jose Florez, Andre Franke, Gad Getz, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Christopher Haiman, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Mikko Kallela, Jaakko Kaprio, Sekar Kathiresan, Bong-Jo Kim, Young Jin Kim, George Kirov, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Terho Lehtimäki, Ruth J.F. Loos, Steven A. Lubitz, Ronald C.W. Ma, Daniel G. MacArthur, Jaume Marrugat, Kari M. Mattila, Steven McCarroll, Mark I McCarthy, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Benjamin M Neale, Peter M Nilsson, Michael C O’Donovan, Dost Ongur, Lorena Orozco, Michael J Owen, Colin N.A. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Ann E. Pulver, Nazneen Rahman, Anne M. Remes, John D. Rioux, Samuli Ripatti, Dan M. Roden, Danish Saleheen, Veikko Salomaa, Nilesh J. Samani, Jeremiah Scharf, Heribert Schunkert, Moore B. Shoemaker, Pamela Sklar, Hilkka Soininen, Harry Soko, Tim Spector, Patrick F. Sullivan, Jaana Suvisaari, E Shyong Tai, Yik Ying Teo, Tuomi Tiinamaija, Ming Tsuang, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, James S Ware, Hugh Watkins, Rinse K Weersma, Maija Wessman, James G. Wilson, Ramnik J. Xavier, Stuart A Cook, Paul J R Barton, Daniel G MacArthur, James S Ware
bioRxiv 543504; doi: https://doi.org/10.1101/543504

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