Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank

Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participa...

Full description

Saved in:

Bibliographic Details
Published in	Nature genetics Vol. 54; no. 3; pp. 240 - 250
Main Authors	Jurgens, Sean J., Choi, Seung Hoan, Morrill, Valerie N., Chaffin, Mark, Pirruccello, James P., Halford, Jennifer L., Weng, Lu-Chen, Nauffal, Victor, Roselli, Carolina, Hall, Amelia W., Oetjens, Matthew T., Lagerman, Braxton, vanMaanen, David P., Aragam, Krishna G., Lunetta, Kathryn L., Haggerty, Christopher M., Lubitz, Steven A., Ellinor, Patrick T.
Format	Journal Article
Language	English
Published	New York Nature Publishing Group US 01.03.2022
Subjects	631/208/457 631/208/514/1948 692/308/2056 692/699/75 Agriculture Animal Genetics and Genomics Biological Specimen Banks Biomedical and Life Sciences Biomedicine Cancer Research Cardiovascular Diseases - epidemiology Cardiovascular Diseases - genetics Carrier Proteins - genetics Diabetes Mellitus, Type 2 - genetics Gene Function Genetic Predisposition to Disease Genetic Variation - genetics Human Genetics Humans United Kingdom United Kingdom
Online Access	Get full text
ISSN	1061-4036 1546-1718 1546-1718
DOI	10.1038/s41588-021-01011-w

Cover

More Information
Summary:	Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete. Here, we analyzed the contribution of rare variants to 57 diseases and 26 cardiometabolic traits, using data from 200,337 UK Biobank participants with whole-exome sequencing. We identified 57 gene-based associations, with broad replication of novel signals in Geisinger MyCode. There was a striking risk associated with mutations in known Mendelian disease genes, including MYBPC3 , LDLR , GCK , PKD1 and TTN . Many genes showed independent convergence of rare and common variant evidence, including an association between GIGYF1 and type 2 diabetes. We identified several large effect associations for height and 18 unique genes associated with blood lipid or glucose levels. Finally, we found that between 1.0% and 2.4% of participants carried rare potentially pathogenic variants for cardiometabolic disorders. These findings may facilitate studies aimed at therapeutics and screening of these common disorders. Analysis of whole-exome sequencing data from over 200,000 individuals in the UK Biobank provides new insights into the contribution of rare variants to cardiometabolic diseases and traits.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work. These authors jointly supervised this work. Author Contributions Statement S.J.J., S.H.C., S.A.L. and P.T.E. conceived and designed the study. S.J.J., S.H.C., V.N.M., M.C., J.P.P and J.L.H. performed data curation and data processing, for data other than the MyCode dataset. S.J.J., S.H.C. and V.N.M. performed statistical analyses, for data other than the MyCode dataset. M.T.O., B.L., D.P.v.M. and C.M.H. performed data curation, data processing and statistical analyses in the MyCode dataset. S.J.J., S.H.C. and M.C. performed data visualization. K.G.A., K.L.L., S.A.L. and P.T.E. supervised the overall study. S.J.J., S.H.C. and P.T.E. drafted the manuscript. L.-C.W., V.N., C.R. and A.W.H. contributed critically to the analysis plan and revisions of the manuscript. All authors critically revised and approved the manuscript. Contributions from consortium members from the Regeneron Genetics Center are provided in the Supplementary Note. A list of consortium authors and their affiliations appear at the end of the paper.
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-021-01011-w