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...

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Published inNature 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
LanguageEnglish
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 AccessGet full text
ISSN1061-4036
1546-1718
1546-1718
DOI10.1038/s41588-021-01011-w

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Abstract 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.
AbstractList 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.
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.
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.
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.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.
Author Pirruccello, James P.
Weng, Lu-Chen
Halford, Jennifer L.
vanMaanen, David P.
Chaffin, Mark
Choi, Seung Hoan
Morrill, Valerie N.
Jurgens, Sean J.
Oetjens, Matthew T.
Haggerty, Christopher M.
Aragam, Krishna G.
Lagerman, Braxton
Roselli, Carolina
Hall, Amelia W.
Lubitz, Steven A.
Nauffal, Victor
Ellinor, Patrick T.
Lunetta, Kathryn L.
AuthorAffiliation 3 Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
4 Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA
2 Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
5 Department of Translational Data Science and Informatics, Geisinger, Danville, PA, USA
6 Regeneron Genetics Center, Tarrytown, NY, USA
10 Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital, Boston, MA, USA
1 Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA
7 NHLBI and Boston University’s Framingham Heart Study, Framingham, MA, USA
8 Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
9 Heart Institute, Geisinger, Danville, PA, USA
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  organization: Cardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cardiovascular Research Center, Massachusetts General Hospital, Demoulas Center for Cardiac Arrhythmias, Massachusetts General Hospital
BackLink https://www.ncbi.nlm.nih.gov/pubmed/35177841$$D View this record in MEDLINE/PubMed
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ContentType Journal Article
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Ferreira, Manuel A R
Mitnaul, Lyndon J
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Widom, Louis
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Reid, Jeffrey G
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Deubler, Andrew
Coppola, Giovanni
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Maxwell, Evan K
Ulloa, Ricardo H
Boutkov, Boris
Eom, Gisu
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Mansfield, Adam J
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Siminovitch, Katherine
Lotta, Luca A
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License 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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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.
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Snippet Cardiometabolic diseases are the leading cause of death worldwide. Despite a known genetic component, our understanding of these diseases remains incomplete....
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631/208/514/1948
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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
Title Analysis of rare genetic variation underlying cardiometabolic diseases and traits among 200,000 individuals in the UK Biobank
URI https://link.springer.com/article/10.1038/s41588-021-01011-w
https://www.ncbi.nlm.nih.gov/pubmed/35177841
https://www.proquest.com/docview/2630919563
https://pubmed.ncbi.nlm.nih.gov/PMC8930703
Volume 54
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