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Nat Commun. 2018 Apr 24;9(1):1613. doi: 10.1038/s41467-018-03911-8.

Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.

Author information

1
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
2
Department of Medicine, Massachusetts General Hospital, Cardiology Division, Harvard Medical School, Boston, MA, 02114, USA.
3
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
4
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
5
Department of Computational Biology & Bioinformatics, Yale Medical School, Yale University, New Haven, MA, 06510, USA.
6
Division of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, 43121, Italy.
7
Associazione per lo Studio Della Trombosi in Cardiologia, Pavia, 27100, Italy.
8
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
9
Deutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, 80333, Germany.
10
University of Ottawa Heart Institute, Ottawa, ON, K1Y4W7, Canada.
11
Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, OX1 2JD, UK.
12
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX1 2JD, UK.
13
Cardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, 08003, Spain.
14
CIBER Enfermedades Cardiovasculares (CIBERCV), Barcelona, 28029, Spain.
15
Facultat de Medicina, Universitat de Vic-Central de Cataluña, Barcelona, VIC, 08500, Spain.
16
Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, LE1 7RH, UK.
17
The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
18
Institute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, 23562, Germany.
19
Department of Public Health and Primary Care, Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB2 0SR, UK.
20
Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.
21
National Institute of Health Research Blood and Transplant; Research Unit in Donor Health and Genomics, University of Cambridge, Cambridge, CB2 1TN, UK.
22
Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, 02115, USA.
23
Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, 37235, USA.
24
Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06510, USA.
25
Department of Emergency Medicine, Yale University, New Haven, CT, 06520, USA.
26
Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, 06510, USA.
27
Department of Biomedical & Saint Luke's Mid America Heart Institute and the Health Informatics, Division of Endocrinology and Metabolism, University of Missouri-Kansas City, Kansas City, MO, 64110, USA.
28
Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan.
29
The Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, 90095, USA.
30
Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, 98195, WA, USA.
31
Cardiovascular Health Research Unit, Kaiser Permanente Washington Health Research Institute, 98101, Seattle, WA, USA.
32
Center for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
33
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
34
Center for Non-Communicable Diseases, Karachi, 74800, Pakistan.
35
Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
36
Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. skathiresan1@mgh.harvard.edu.
37
Department of Medicine, Massachusetts General Hospital, Cardiology Division, Harvard Medical School, Boston, MA, 02114, USA. skathiresan1@mgh.harvard.edu.
38
Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA. skathiresan1@mgh.harvard.edu.

Abstract

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

PMID:
29691411
PMCID:
PMC5915445
DOI:
10.1038/s41467-018-03911-8
[Indexed for MEDLINE]
Free PMC Article

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