Abstract

Upstream open reading frames (uORFs) are tissue-specific cis-regulators of protein translation. Isolated reports have shown that variants that create or disrupt uORFs can cause disease. Here, in a systematic genome-wide study using 15,708 whole genome sequences, we show that variants that create new upstream start codons, and variants disrupting stop sites of existing uORFs, are under strong negative selection. This selection signal is significantly stronger for variants arising upstream of genes intolerant to loss-of-function variants. Furthermore, variants creating uORFs that overlap the coding sequence show signals of selection equivalent to coding missense variants. Finally, we identify specific genes where modification of uORFs likely represents an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in neurofibromatosis. Our results highlight uORF-perturbing variants as an under-recognised functional class that contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data in studying non-coding variant classes.

Genome Aggregation Database Consortium

Carlos A. Aguilar Salinas21, Tariq Ahmad22, Christine M. Albert23,24, Diego Ardissino25, Gil Atzmon26,27,John Barnard28, Laurent Beaugerie29, Emelia J. Benjamin30,31,32, Michael Boehnke33, Lori L. Bonnycastle34,Erwin P. Bottinger35, Donald W. Bowden36,37,38, Matthew J. Bown39,40, John C. Chambers41,42,43,Juliana C. Chan44, Daniel Chasman23,45, Judy Cho35, Mina K. Chung46, Bruce Cohen45,47, Adolfo Correa48,Dana Dabelea49, Mark J. Daly3,4,18, Dawood Darbar50, Ravindranath Duggirala51, Josée Dupuis52,53,Patrick T. Ellinor3,54, Roberto Elosua55,56,57, Jeanette Erdmann58,59,60, Tõnu Esko3,61, Martti Färkkilä62,Jose Florez63, Andre Franke64, Gad Getz45,65,66, Benjamin Glaser67, Stephen J. Glatt68, David Goldstein69,70,Clicerio Gonzalez71, Leif Groop72,73, Christopher Haiman74, Craig Hanis75, Matthew Harms76,77,Mikko Hiltunen78, Matti M. Holi79, Christina M. Hultman80,81, Mikko Kallela82, Jaakko Kaprio73,83,Sekar Kathiresan45,84,85, Bong-Jo Kim86, Young Jin Kim86, George Kirov87, Jaspal Kooner42,43,88,Seppo Koskinen89, Harlan M. Krumholz90, Subra Kugathasan91, Soo Heon Kwak92, Markku Laakso93,94,Terho Lehtimäki95, Ruth J.F. Loos35,96, Steven A. Lubitz3,56, Ronald C.W. Ma44,97,98, Jaume Marrugat58,99,Kari M. Mattila95, Steven McCarroll51,100, Mark I. McCarthy101,102,103, Dermot McGovern104,Ruth McPherson105, James B. Meigs45,106,107, Olle Melander108, Andres Metspalu61, Benjamin M. Neale3,4,Peter M. Nilsson109, Michael C. O’Donovan87, Dost Ongur45,47, Lorena Orozco110, Michael J. Owen87,Colin N.A. Palmer111, Aarno Palotie4,51,73, Kyong Soo Park92,112, Carlos Pato113, Ann E. Pulver114,Nazneen Rahman115, Anne M. Remes116, John D. Rioux117,118, Samuli Ripatti73,83,119, Dan M. Roden120,121,Danish Saleheen122,123,124, Veikko Salomaa125, Nilesh J. Samani39,40, Jeremiah Scharf3,18,84,Heribert Schunkert126,127, Moore B. Shoemaker128, Pamela Sklar129,130,131, Hilkka Soininen132, Harry Sokol29,Tim Spector133, Patrick F. Sullivan80,134, Jaana Suvisaari125, E. Shyong Tai135,136,137, Yik Ying Teo136,138,139,Tuomi Tiinamaija73,140,141, Ming Tsuang142,143, Dan Turner144, Teresa Tusie-Luna145,146, Erkki Vartiainen83,Hugh Watkins147, Rinse K. Weersma148, Maija Wessman73,140, James G. Wilson149, Ramnik J. Xavier150,151 21Unidad de Investigacion de Enfermedades Metabolicas, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City, Mexico.22PeninsulaCollege of Medicine and Dentistry, Exeter EX2 4TH, UK.23Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA 02115,USA.24Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.25Departmentof Cardiology University Hospital, 43100 Parma, Italy.26Department of Biology, Faculty of Natural Sciences, University of Haifa, 3498838 Haifa,Israel.27Departments of Medicine and Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.28Department of Quantitative HealthSciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44122, USA.29APHP, Gastroenterology Department, Saint Antoine Hospital,Sorbonne Université, Paris, France.30NHLBI and Boston University’s Framingham Heart Study, Framingham, MA 01701, USA.31Department ofMedicine, Boston University School of Medicine, Boston, MA 02118, USA.32Department of Epidemiology, Boston University School of Public Health,Boston, MA 02118, USA.33Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI 48109, USA.34National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.35The Charles Bronfman Institute forPersonalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.36Department of Biochemistry, Wake Forest School ofMedicine, Winston-Salem, NC 27101, USA.37Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine,Winston-Salem, NC 27101, USA.38Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC 27101, USA.39Departmentof Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK.40NIHR Leicester Biomedical Research Centre, Glenfield Hospital,Leicester LE3 9QP, UK.41Department of Epidemiology and Biostatistics, Imperial College London, London SW7 2BX, UK.42Department of Cardiology, Ealing Hospital NHS Trust, Southall UB1 3HW, UK.43Imperial College Healthcare NHS Trust, Imperial College London, London SW72BX, UK.44Department of Medicine and Therapeutics, The Chinese University of Hong Kong, 999077 Hong Kong, China.45Department ofMedicine, Harvard Medical School, Boston, MA 02115, USA.46Departments of Cardiovascular Medicine, Cellular and Molecular Medicine,Molecular Cardiology, and Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195, USA.47McLean Hospital, Belmont, MA 02478,USA.48Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.49Department of Epidemiology, ColoradoSchool of Public Health, Aurora, Colorado 80246, USA.50Department of Medicine and Pharmacology, University of Illinois at Chicago, Chicago, IL60607, USA.51Department of Genetics, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.52Department of Biostatistics, BostonUniversity School of Public Health, Boston, MA 02118, USA.53National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham,MA 01702, USA.54Cardiac Arrhythmia Service and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA.55Cardiovascular Epidemiology and Genetics, Hospital del Mar Medical Research Institute (IMIM), Barcelona, Catalonia, Spain.56CIBER CV,Barcelona, Catalonia, Spain.57Departament of Medicine, Medical School, University of Vic-Central University of Catalonia, Catalonia 08500, Spain.58Institute for Cardiogenetics, University of Lübeck, Lübeck 23562, Germany.59DZHK (German Research Centre for Cardiovascular Research)partner site Hamburg/Lübeck/Kiel, 23562 Lübeck, Germany.60University Heart Center Lübeck, 23562 Lübeck, Germany.61Estonian GenomeCenter, Institute of Genomics, University of Tartu, Tartu 50090, Estonia.62Clinic of Gastroenterology, Helsinki University and Helsinki UniversityHospital, FL 00014 Helsinki, Finland.63Diabetes Unit and Center for Genomic Medicine, Massachusetts General Hospital; Programs in Metabolismand Medical and Population Genetics, Broad Institute; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.64Institute ofClinical Molecular Biology (IKMB), Christian-Albrechts-University of Kiel, Kiel 24118, Germany.65Bioinformatics Program, Department of Pathology,MGH Cancer Center, Boston 02114, USA.66Cancer Genome Computational Analysis, Broad Institute, Cambridge 02142, USA.67Endocrinology andMetabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.68Department of Psychiatry and Behavioral Sciences,SUNY Upstate Medical University, Syracuse, NY 13421, USA.69Institute for Genomic Medicine, Columbia University Medical Center, HammerHealth Sciences, 1408, 701 West 168th Street, New York, NY 10032, USA.70Department of Genetics & Development, Columbia University MedicalCenter, Hammer Health Sciences, 1602, 701 West 168th Street, New York, NY 10032, USA.71Centro de Investigacion en Salud Poblacional InstitutoNacional de Salud Publica MEXICO, Cuernavace 62100, Mexico.72Lund University, SE-221 00 Lund, Sweden.73Institute for Molecular MedicineFinland (FIMM), HiLIFE, University of Helsinki, FL 00014 Helsinki, Finland.74Lund University Diabetes Centre, SE-221 00 Lund, Sweden.75HumanGenetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.76Department of Neurology, ColumbiaUniversity, New York 10032, USA.77Institute of Genomic Medicine, Columbia University, New York 10032, USA.78Institute of Biomedicine,University of Eastern Finland, Kuopio FI-80101, Finland.79Department of Psychiatry, PL 320, Helsinki University Central Hospital, Lapinlahdentie, 00180, Helsinki, Finland.80Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden.81Icahn School ofMedicine at Mount Sinai, New York, NY 10029, USA.82Department of Neurology, Helsinki University Central Hospital, Fl 00290 Helsinki, Finland.83Department of Public Health, Faculty of Medicine, University of Helsinki, FL 00014 Helsinki, Finland.84Center for Genomic Medicine,Massachusetts General Hospital, Boston, MA 02114, USA.85Cardiovascular Disease Initiative and Program in Medical and Population Genetics,Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.86Center for Genome Science, Korea National Institute of Health,Chungcheongbuk-do, Republic of Korea.87MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, HadynEllis Building, Maindy Road, Cardiff CF24 4HQ, UK.88National Heart and Lung Institute, Cardiovascular Sciences, Imperial College London,Hammersmith Campus, London SW7 2BX, UK.89Department of Health, THL-National Institute for Health and Welfare, 00271 Helsinki, Finland.90Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT 06510, USA.91Division ofPediatric Gastroenterology, Emory University School of Medicine, Atlanta, GA 30322, USA.92Department of Internal Medicine, Seoul NationalUniversity Hospital, Seoul, Republic of Korea.93Institute of Clinical Medicine, The University of Eastern Finland, Kuopio, Finland.94Kuopio UniversityHospital, Kuopio 70210, Finland.95Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center-Tampere,Faculty of Medicine and Health Technology, Tampere University, FI-33014 Tampere, Finland.96The Mindich Child Health and DevelopmentInstitute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.97Li Ka Shing Institute of Health Sciences, The Chinese University ofHong Kong, Hong Kong, China.98Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong, China.99Cardiovascular Research REGICOR Group, Hospital del Mar Medical Research Institute (IMIM), Barcelona 08003 Catalonia, Spain.100Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.101Oxford Centre for Diabetes, Endocrinology and Metabolism,University of Oxford, Churchill Hospital, Old Road, Headington, Oxford OX3 7LJ, UK.102Wellcome Centre for Human Genetics, University of Oxford,Roosevelt Drive, Oxford OX3 7BN, UK.103Oxford NIHR Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, JohnRadcliffe Hospital, Oxford OX3 9DU, UK.104F Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-SinaiMedical Center, Los Angeles, CA 90048, USA.105Atherogenomics Laboratory, University of Ottawa Heart Institute, Ottawa, ON K1Y 4W7,Canada.106Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.107Program in Population and MedicalGenetics, Broad Institute, Cambridge, MA 02142, USA.108Department of Clinical Sciences, University Hospital Malmo Clinical Research Center,Lund University, SE-221 00 Malmo, Sweden.109Department of Clinical Sciences, Lund University, Skane University Hospital, SE-221 00 Malmo,Sweden.110Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico.111Medical Research Institute, Ninewells Hospitaland Medical School, University of Dundee, Dundee DD1 4HN, UK.112Department of Molecular Medicine and Biopharmaceutical Sciences, GraduateSchool of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea.113Department of Psychiatry, Keck School ofMedicine at the University of Southern California, Los Angeles, CA 90033, USA.114Department of Psychiatry and Behavioral Sciences, JohnsHopkins University School of Medicine, Baltimore, MD 20105, USA.115Division of Genetics and Epidemiology, Institute of Cancer Research, LondonSM2 5NG, UK.116Medical Research Center, Oulu University Hospital, Oulu, Finland and Research Unit of Clinical Neuroscience, Neurology,University of Oulu, FI-90014 Oulu, Finland.117Research Center, Montreal Heart Institute, Montreal, QC H1T 1C8, Canada.118Department ofMedicine, Faculty of Medicine, Université de Montréal, Montréal H3T 1J4 Québec, Canada.119Broad Institute of MIT and Harvard, Cambridge, MA02142, USA.120Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37212, USA.121Department of Medicine,Vanderbilt University Medical Center, Nashville, TN 37212, USA.122Department of Biostatistics and Epidemiology, Perelman School of Medicine atthe University of Pennsylvania, Philadelphia, PA 19104, USA.123Department of Medicine, Perelman School of Medicine at the University ofPennsylvania, Philadelphia, PA 19104, USA.124Center for Non-Communicable Diseases, Karachi 75300, Pakistan.125National Institute for Healthand Welfare, Helsinki FI 00271, Finland.126Deutsches Herzzentrum München, München 80636, Germany.127Technische Universität München,München 80333, Germany.128Division of Cardiovascular Medicine, Nashville VA Medical Center and Vanderbilt University, School of Medicine,Nashville, TN 37232-8802, USA.129Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.130Departmentof Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.131Institute for Genomics and MultiscaleBiology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.132Institute of Clinical Medicine, neurology, University of EasternFinland, Kuopio, Finland.133Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK.134Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA.135Saw Swee Hock School of Public Health, NationalUniversity of Singapore, National University Health System, Singapore 117549, Singapore.136Department of Medicine, Yong Loo Lin School ofMedicine, National University of Singapore, Singapore 117597, Singapore.137Duke-NUS Graduate Medical School, Singapore 169857, Singapore.138Life Sciences Institute, National University of Singapore, Singapore 117456, Singapore.139Department of Statistics and Applied Probability,National University of Singapore, Singapore 119077, Singapore.140Folkhälsan Institute of Genetics, Folkhälsan Research Center, Helsinki, Finland.141HUCH Abdominal Center, Helsinki University Hospital, Helsinki 00260, Finland.142Center for Behavioral Genomics, Department of Psychiatry,University of California, San Diego, CA 94720, USA.143Institute of Genomic Medicine, University of California, San Diego, CA 94720, USA.144JulietKeidan Institute of Pediatric Gastroenterology, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel.145Instituto deInvestigaciones Biomédicas UNAM, Mexico City 04510, Mexico.146Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán MexicoCity, Mexico City 14080, Mexico.147Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK.148Department ofGastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen 9713 GZ, The Netherlands.149Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA.150Program in Infectious Diseaseand Microbiome, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.151Center for Computational and Integrative Biology,Massachusetts General Hospital, Boston, MA 02114, U