ArticleNature communications2018
Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.
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Article in Nature communications, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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51citing papers in PubMed, 1 pooled it
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The contribution of common and rare genetic variants to variation in metabolic traits in 288,137 East Asians.Nature communications · 2022Pooled it
- Atlas of glomerular disease-specific genetic effects on blood transcriptome.medRxiv : the preprint server for health sciences · 2026Article
- How loss-of-function mutations inJournal of translational autoimmunity · 2026Review
- Functional insights into dispensable genes using genome-wide loss-of-function burden tests in Arabidopsis.The Plant cell · 2026Article
- Adenosine-to-Inosine (A-to-I) RNA Editing by ADAR1 to Control RNA Sensing in Cardiovascular Disease.Arteriosclerosis, thrombosis, and vascular biology · 2026Review
- Interactions between lipid droplets and mitochondria in metabolic diseases.Lipids in health and disease · 2025Review
- Smooth muscle expression of RNA editing enzyme ADAR1 controls activation of the RNA sensor MDA5 in atherosclerosis.Nature cardiovascular research · 2025Article
- Leveraging genetics to understand ADAR1-mediated RNA editing in health and disease.Nature reviews. Genetics · 2025Review
- The Orphan Receptor GPR151: Discovery, Expression, and Emerging Biological Significance.ACS chemical neuroscience · 2025Review
- Hypometric genetics: Improved power in genetic discovery by incorporating quality control flags.American journal of human genetics · 2024Article
- Drug-target Mendelian randomisation applied to metabolic dysfunction-associated steatotic liver disease: opportunities and challenges.eGastroenterology · 2024Review
- The Role of Genetics in Advancing Cardiometabolic Drug Development.Current atherosclerosis reports · 2024Review
- Multifaceted roles of RNA editing enzyme ADAR1 in innate immunity.RNA (New York, N.Y.) · 2024Article
- Review
- STZ-induced hyperglycemia differentially influences mitochondrial distribution and morphology in the habenulointerpeduncular circuit.Frontiers in cellular neuroscience · 2024Article
- Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts.Human genetics · 2023Article
- Mendelian randomization as a tool to inform drug development using human genetics.Cambridge prisms. Precision medicine · 2023Review
- Beyond apples and pears: sex-specific genetics of body fat percentage.Frontiers in endocrinology · 2023Article
- G protein-coupled receptor 151 regulates glucose metabolism and hepatic gluconeogenesis.Nature communications · 2022Article
- Article
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Authors and funding
41 authors.
Connor A EmdinCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.ORCID http://orcid.org/0000-0002-2385-8259
Amit V KheraCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Mark ChaffinCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.ORCID http://orcid.org/0000-0002-1234-5562
Derek KlarinCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Pradeep NatarajanCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Krishna AragamCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Mary HaasCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Alexander BickCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Seyedeh M ZekavatCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Akihiro NomuraCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Diego ArdissinoDivision of Cardiology, Azienda Ospedaliero-Universitaria di Parma, Parma, 43121, Italy.
James G WilsonDepartment of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, 39216, USA.
Heribert SchunkertDeutsches Herzzentrum München, Technische Universität München, Deutsches Zentrum für Herz-Kreislauf-Forschung, München, 80333, Germany.
Ruth McPhersonUniversity of Ottawa Heart Institute, Ottawa, ON, K1Y4W7, Canada.
Hugh WatkinsRadcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, Oxford, OX1 2JD, UK.
Roberto ElosuaCardiovascular Epidemiology and Genetics, Hospital del Mar Research Institute, Barcelona, 08003, Spain.
Matthew J BownDepartment of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, LE1 7RH, UK.
Nilesh J SamaniDepartment of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Leicester, LE1 7RH, UK.
Usman BaberThe Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
Jeanette ErdmannInstitute for Integrative and Experimental Genomics, University of Lübeck, Lübeck, 23562, Germany.ORCID http://orcid.org/0000-0002-4486-6231
Namrata GuptaProgram in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
John DaneshDepartment of Public Health and Primary Care, Cardiovascular Epidemiology Unit, University of Cambridge, Cambridge, CB2 0SR, UK.
Daniel ChasmanCenter for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, 02115, USA.
Paul RidkerCenter for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Boston, 02115, USA.
Joshua DennyDepartment of Biomedical Informatics, Vanderbilt University, Nashville, TN, 37235, USA.
Lisa BastaracheDepartment of Biomedical Informatics, Vanderbilt University, Nashville, TN, 37235, USA.
Judith H LichtmanDepartment of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06510, USA.
Gail D'OnofrioDepartment of Emergency Medicine, Yale University, New Haven, CT, 06520, USA.
Jennifer MatteraCenter for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, 06510, USA.
John A SpertusDepartment 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.
Wayne H-H SheuDepartment of Internal Medicine, Taichung Veterans General Hospital, Taichung, 40705, Taiwan.
Kent D TaylorThe Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, 90095, USA.
Bruce M PsatyCardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, 98195, WA, USA.
Stephen S RichCenter for Public Health Genomics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
Wendy PostDivision of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Jerome I RotterThe Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, 90095, USA.
Yii-Der Ida ChenThe Institute for Translational Genomics and Population Sciences, LABioMed and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, CA, 90095, USA.
Harlan KrumholzCenter for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, 06510, USA.
Danish SaleheenCenter for Non-Communicable Diseases, Karachi, 74800, Pakistan.ORCID http://orcid.org/0000-0001-6193-020X
Stacey GabrielProgram in Medical and Population Genetics, Broad Institute, Cambridge, MA, 02142, USA.
Sekar KathiresanCenter for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. skathiresan1@mgh.harvard.edu.ORCID http://orcid.org/0000-0002-6724-032X
Funding
UCLA Clinical Translational Science InstituteUL1TR001881 · NCATS · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI ARLEEN F. BROWN, ARASH NAEIM · 2016 to 2026
$118.1MCenter for Common Disease GeneticsUM1HG008895 · NHGRI · BROAD INSTITUTE, INC. · PI DALY, MARK JOSEPH, GABRIEL, STACEY · 2016 to 2020
$111.2MInstitute for Clinical and Translational ResearchUL1TR001079 · NCATS · JOHNS HOPKINS UNIVERSITY · PI FORD, DANIEL ERNEST · 2013 to 2017
$60.1MMEDICAL SCIENTIST TRAINING PROGRAMT32GM007205 · NIGMS · YALE UNIVERSITY · PI KAZMIERCZAK, BARBARA I · 1985 to 2019
$42.9MTransgenic & Knock-out MouseP30DK063491 · NIDDK · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI PETER J TONTONOZ · 2003 to 2026
$40.4MTracking and Evaluation CoreU54GM115428 · NIGMS · UNIVERSITY OF MISSISSIPPI MED CTR · PI HALL, JOHN E · 2016 to 2025
$38.2MWake Forest Clinical and Translational Science AwardUL1TR001420 · NCATS · WAKE FOREST UNIVERSITY HEALTH SCIENCES · PI ARD, JAMY D, FOLEY, KRISTIE L · 2015 to 2023
$32.3MWomen's Health Study: Continued Follow-upR01CA047988 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI BURING, JULIE E., LEE, I-MIN · 1991 to 2014
$28.2MBuilding on GWAS for NHLBI-disease: the CHARGE consortiumRC2HL102419 · NHLBI · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · PI BOERWINKLE, ERIC A. · 2009 to 2010
$27.6MClinical and Translational Science AwardUL1TR000040 · NCATS · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI GINSBERG, HENRY N · 2012 to 2015
$26.2MYoung Women With Acute Myocardial InfarctionR01HL081153 · NHLBI · YALE UNIVERSITY · PI KRUMHOLZ, HARLAN MARC · 2007 to 2012
$10.6MHarvard Clinical and Translational Science CenterKL2TR001100 · NCATS · HARVARD MEDICAL SCHOOL · PI NADLER, LEE MARSHALL · 2013 to 2017
$8.5MBritish Heart Foundation CH/12/2/29428British Heart Foundation CS/14/2/30841British Heart Foundation RG/08/014/24067British Heart Foundation RG/13/13/30194British Heart Foundation RG/16/4/32218Medical Research Council G0501792Medical Research Council G0601284Medical Research Council G0700463Medical Research Council G0800270Medical Research Council MC_PC_17228Medical Research Council MC_QA137853Medical Research Council MR/L003120/1Medical Research Council MR/P013880/1Medical Research Council MR/P02811X/1NCATS NIH HHS KL2 TR001100NCATS NIH HHS UL1 TR000040NCATS NIH HHS UL1 TR001079NCATS NIH HHS UL1 TR001420NCATS NIH HHS UL1 TR001881NCI NIH HHS R01 CA047988NCI NIH HHS UM1 CA182913NHGRI NIH HHS UM1 HG008895NHLBI NIH HHS HHSN268201100005CNHLBI NIH HHS HHSN268201100005GNHLBI NIH HHS HHSN268201100005INHLBI NIH HHS HHSN268201100006CNHLBI NIH HHS HHSN268201100007CNHLBI NIH HHS HHSN268201100007INHLBI NIH HHS HHSN268201100008CNHLBI NIH HHS HHSN268201100008INHLBI NIH HHS HHSN268201100009CNHLBI NIH HHS HHSN268201100009INHLBI NIH HHS HHSN268201100010CNHLBI NIH HHS HHSN268201100011CNHLBI NIH HHS HHSN268201100011INHLBI NIH HHS HHSN268201100012CNHLBI NIH HHS HHSN268201500003CNHLBI NIH HHS HHSN268201500003INHLBI NIH HHS K08 HL140203NHLBI NIH HHS N01 HC095159NHLBI NIH HHS N01 HC095160NHLBI NIH HHS N01 HC095161NHLBI NIH HHS N01 HC095162NHLBI NIH HHS N01 HC095163NHLBI NIH HHS N01 HC095164NHLBI NIH HHS N01 HC095165NHLBI NIH HHS N01 HC095166NHLBI NIH HHS N01 HC095167NHLBI NIH HHS N01 HC095168NHLBI NIH HHS N01 HC095169NHLBI NIH HHS R01 HL043851NHLBI NIH HHS R01 HL080467NHLBI NIH HHS R01 HL081153NHLBI NIH HHS RC2 HL102419NIDDK NIH HHS P30 DK063491NIGMS NIH HHS T32 GM007205NIGMS NIH HHS U54 GM115428
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.
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Databases, GeneticDiabetes Mellitus, Type 2DiseaseGene FrequencyGenetic TestingGenetic VariationHumansObesityPhenotypeProteinsRespiratory HypersensitivityUnited KingdomProteins
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