Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Regeneron Genetics Center; Sonia Shah; Albert Henry; Carolina Roselli; Honghuang Lin; Garðar Sveinbjörnsson; Ghazaleh Fatemifar; Åsa K. Hedman; Jemma B. Wilk; Michael P. Morley; Mark D. Chaffin; Anna Helgadottir; Niek Verweij; Abbas Dehghan; Peter Almgren; Charlotte Andersson; Krishna G. Aragam; Johan Ärnlöv; Joshua D. Backman; Mary L. Biggs; Heather L. Bloom; Jeffrey Brandimarto; Michael R. Brown; Leonard Buckbinder; David J. Carey; Daniel I. Chasman; Xing Chen; Xu Chen; Jonathan Chung; William Chutkow; James P. Cook; Graciela E. Delgado; Spiros Denaxas; Alexander S. Doney; Marcus Dörr; Samuel C. Dudley; Michael E. Dunn; Gunnar Engström; Tõnu Esko; Stephan B. Felix; Chris Finan; Ian Ford; Ify R. Mordi; Andrew D. Morris; Andrew P. Morris; Colin N. A. Palmer; Helen M. Parry; Nicholas L. Smith; Abirami Veluchamy; John J. V. McMurray; Chim C. Lang; R. Thomas Lumbers

doi:10.1038/s41467-019-13690-5

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Regeneron Genetics Center, Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Garðar Sveinbjörnsson, Ghazaleh Fatemifar, Åsa K. Hedman, Jemma B. Wilk, Michael P. Morley, Mark D. Chaffin, Anna Helgadottir, Niek Verweij, Abbas Dehghan, Peter Almgren, Charlotte Andersson, Krishna G. Aragam, Johan Ärnlöv, Joshua D. Backman, Mary L. BiggsHeather L. Bloom, Jeffrey Brandimarto, Michael R. Brown, Leonard Buckbinder, David J. Carey, Daniel I. Chasman, Xing Chen, Xu Chen, Jonathan Chung, William Chutkow, James P. Cook, Graciela E. Delgado, Spiros Denaxas, Alexander S. Doney, Marcus Dörr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engström, Tõnu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Ify R. Mordi, Andrew D. Morris, Andrew P. Morris, Colin N. A. Palmer, Helen M. Parry, Nicholas L. Smith, Abirami Veluchamy, John J. V. McMurray, Chim C. Lang, R. Thomas Lumbers (Lead / Corresponding author)

Population Health and Genomics

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Abstract

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

Original language	English
Article number	163
Number of pages	12
Journal	Nature Communications
Volume	11
DOIs	https://doi.org/10.1038/s41467-019-13690-5
Publication status	Published - 9 Jan 2020

Keywords

Cardiovascular genetics
Epidemiology
Genome-wide association studies
Heart failure

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-019-13690-5Licence: CC BY

Final Published VersionFinal published version, 2.16 MBLicence: CC BY

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Regeneron Genetics Center, Shah, S., Henry, A., Roselli, C., Lin, H., Sveinbjörnsson, G., Fatemifar, G., Hedman, Å. K., Wilk, J. B., Morley, M. P., Chaffin, M. D., Helgadottir, A., Verweij, N., Dehghan, A., Almgren, P., Andersson, C., Aragam, K. G., Ärnlöv, J., Backman, J. D., ... Lumbers, R. T. (2020). Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nature Communications, 11, Article 163. https://doi.org/10.1038/s41467-019-13690-5

@article{5c596ad8e844499fa1c91b1e86181a03,

title = "Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure",

abstract = "Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.",

keywords = "Cardiovascular genetics, Epidemiology, Genome-wide association studies, Heart failure",

author = "{Regeneron Genetics Center} and Sonia Shah and Albert Henry and Carolina Roselli and Honghuang Lin and Gar{\dh}ar Sveinbj{\"o}rnsson and Ghazaleh Fatemifar and Hedman, {{\AA}sa K.} and Wilk, {Jemma B.} and Morley, {Michael P.} and Chaffin, {Mark D.} and Anna Helgadottir and Niek Verweij and Abbas Dehghan and Peter Almgren and Charlotte Andersson and Aragam, {Krishna G.} and Johan {\"A}rnl{\"o}v and Backman, {Joshua D.} and Biggs, {Mary L.} and Bloom, {Heather L.} and Jeffrey Brandimarto and Brown, {Michael R.} and Leonard Buckbinder and Carey, {David J.} and Chasman, {Daniel I.} and Xing Chen and Xu Chen and Jonathan Chung and William Chutkow and Cook, {James P.} and Delgado, {Graciela E.} and Spiros Denaxas and Doney, {Alexander S.} and Marcus D{\"o}rr and Dudley, {Samuel C.} and Dunn, {Michael E.} and Gunnar Engstr{\"o}m and T{\~o}nu Esko and Felix, {Stephan B.} and Chris Finan and Ian Ford and Mordi, {Ify R.} and Morris, {Andrew D.} and Morris, {Andrew P.} and Palmer, {Colin N. A.} and Parry, {Helen M.} and Smith, {Nicholas L.} and Abirami Veluchamy and McMurray, {John J. V.} and Lang, {Chim C.} and Lumbers, {R. Thomas}",

year = "2020",

month = jan,

day = "9",

doi = "10.1038/s41467-019-13690-5",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Regeneron Genetics Center, Shah, S, Henry, A, Roselli, C, Lin, H, Sveinbjörnsson, G, Fatemifar, G, Hedman, ÅK, Wilk, JB, Morley, MP, Chaffin, MD, Helgadottir, A, Verweij, N, Dehghan, A, Almgren, P, Andersson, C, Aragam, KG, Ärnlöv, J, Backman, JD, Biggs, ML, Bloom, HL, Brandimarto, J, Brown, MR, Buckbinder, L, Carey, DJ, Chasman, DI, Chen, X, Chen, X, Chung, J, Chutkow, W, Cook, JP, Delgado, GE, Denaxas, S, Doney, AS, Dörr, M, Dudley, SC, Dunn, ME, Engström, G, Esko, T, Felix, SB, Finan, C, Ford, I, Mordi, IR, Morris, AD, Morris, AP, Palmer, CNA, Parry, HM, Smith, NL, Veluchamy, A, McMurray, JJV, Lang, CC & Lumbers, RT 2020, 'Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure', Nature Communications, vol. 11, 163. https://doi.org/10.1038/s41467-019-13690-5

TY - JOUR

T1 - Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

AU - Regeneron Genetics Center

AU - Shah, Sonia

AU - Henry, Albert

AU - Roselli, Carolina

AU - Lin, Honghuang

AU - Sveinbjörnsson, Garðar

AU - Fatemifar, Ghazaleh

AU - Hedman, Åsa K.

AU - Wilk, Jemma B.

AU - Morley, Michael P.

AU - Chaffin, Mark D.

AU - Helgadottir, Anna

AU - Verweij, Niek

AU - Dehghan, Abbas

AU - Almgren, Peter

AU - Andersson, Charlotte

AU - Aragam, Krishna G.

AU - Ärnlöv, Johan

AU - Backman, Joshua D.

AU - Biggs, Mary L.

AU - Bloom, Heather L.

AU - Brandimarto, Jeffrey

AU - Brown, Michael R.

AU - Buckbinder, Leonard

AU - Carey, David J.

AU - Chasman, Daniel I.

AU - Chen, Xing

AU - Chen, Xu

AU - Chung, Jonathan

AU - Chutkow, William

AU - Cook, James P.

AU - Delgado, Graciela E.

AU - Denaxas, Spiros

AU - Doney, Alexander S.

AU - Dörr, Marcus

AU - Dudley, Samuel C.

AU - Dunn, Michael E.

AU - Engström, Gunnar

AU - Esko, Tõnu

AU - Felix, Stephan B.

AU - Finan, Chris

AU - Ford, Ian

AU - Mordi, Ify R.

AU - Morris, Andrew D.

AU - Morris, Andrew P.

AU - Palmer, Colin N. A.

AU - Parry, Helen M.

AU - Smith, Nicholas L.

AU - Veluchamy, Abirami

AU - McMurray, John J. V.

AU - Lang, Chim C.

AU - Lumbers, R. Thomas

PY - 2020/1/9

Y1 - 2020/1/9

N2 - Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

AB - Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies.

KW - Cardiovascular genetics

KW - Epidemiology

KW - Genome-wide association studies

KW - Heart failure

UR - http://www.scopus.com/inward/record.url?scp=85077697294&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-13690-5

DO - 10.1038/s41467-019-13690-5

M3 - Article

C2 - 31919418

AN - SCOPUS:85077697294

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

M1 - 163

ER -

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Abstract

Keywords

ASJC Scopus subject areas

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Identifying Novel Opportunities for Translational Research, Precision Medicine and Drug Repurposing in Cardiovascular Disease using Pharmacoepidemiology, Genetic Epidemiology and Bioinformatics

Lang, Chim

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Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Identifying Novel Opportunities for Translational Research, Precision Medicine and Drug Repurposing in Cardiovascular Disease using Pharmacoepidemiology, Genetic Epidemiology and Bioinformatics

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Lang, Chim

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