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

Regeneron Genetics Ctr; Sonia Shah; Albert Henry; Carolina Roselli; Honghuang Lin; Gardar Sveinbjornsson; Ghazaleh Fatemifar; Asa 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 Arnlov; 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 Doerr; Samuel C. Dudley; Michael E. Dunn; Gunnar Engstrom; Tonu Esko; Stephan B. Felix; Chris Finan; Ian Ford; Mohsen Ghanbari; Sahar Ghasemi; Vilmantas Giedraitis; Franco Giulianini; John S. Gottdiener; Pim van der Harst; Adriaan A. Voors; Jing Hua Zhao; Folkert W. Asselbergs

doi:10.1038/s41467-019-13690-5

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

Regeneron Genetics Ctr, Sonia Shah, Albert Henry, Carolina Roselli, Honghuang Lin, Gardar Sveinbjornsson, Ghazaleh Fatemifar, Asa 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 Arnlov, 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 Doerr, Samuel C. Dudley, Michael E. Dunn, Gunnar Engstrom, Tonu Esko, Stephan B. Felix, Chris Finan, Ian Ford, Mohsen Ghanbari, Sahar Ghasemi, Vilmantas Giedraitis, Franco Giulianini, John S. Gottdiener, Pim van der Harst, Adriaan A. Voors, Jing Hua Zhao, Folkert W. Asselbergs

Cardiovascular Centre (CVC)

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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
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13690-5
Publication status	Published - 9-Jan-2020

Keywords

RISK
EPIDEMIOLOGY
METAANALYSIS
DISEASE
LOCI
HYPERTENSION
IMPUTATION
RESOURCE
CATALOG
OBESITY

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Regeneron Genetics Ctr, Shah, S., Henry, A., Roselli, C., Lin, H., Sveinbjornsson, G., Fatemifar, G., Hedman, A. K., Wilk, J. B., Morley, M. P., Chaffin, M. D., Helgadottir, A., Verweij, N., Dehghan, A., Almgren, P., Andersson, C., Aragam, K. G., Arnlov, J., Backman, J. D., ... Asselbergs, F. W. (2020). Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure. Nature Communications, 11(1), Article 163. https://doi.org/10.1038/s41467-019-13690-5

@article{57d9212a0d4440d5b3f11974cfbf726b,

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 = "RISK, EPIDEMIOLOGY, METAANALYSIS, DISEASE, LOCI, HYPERTENSION, IMPUTATION, RESOURCE, CATALOG, OBESITY",

author = "{Regeneron Genetics Ctr} and Sonia Shah and Albert Henry and Carolina Roselli and Honghuang Lin and Gardar Sveinbjornsson and Ghazaleh Fatemifar and Hedman, {Asa 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 Arnlov 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 Doerr and Dudley, {Samuel C.} and Dunn, {Michael E.} and Gunnar Engstrom and Tonu Esko and Felix, {Stephan B.} and Chris Finan and Ian Ford and Mohsen Ghanbari and Sahar Ghasemi and Vilmantas Giedraitis and Franco Giulianini and Gottdiener, {John S.} and {van der Harst}, Pim and Voors, {Adriaan A.} and Zhao, {Jing Hua} and Asselbergs, {Folkert W.}",

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 Publishing Group",

number = "1",

}

Regeneron Genetics Ctr, Shah, S, Henry, A, Roselli, C, Lin, H, Sveinbjornsson, G, Fatemifar, G, Hedman, AK, Wilk, JB, Morley, MP, Chaffin, MD, Helgadottir, A, Verweij, N, Dehghan, A, Almgren, P, Andersson, C, Aragam, KG, Arnlov, 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, Doerr, M, Dudley, SC, Dunn, ME, Engstrom, G, Esko, T, Felix, SB, Finan, C, Ford, I, Ghanbari, M, Ghasemi, S, Giedraitis, V, Giulianini, F, Gottdiener, JS, van der Harst, P , Voors, AA, Zhao, JH & Asselbergs, FW 2020, 'Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure', Nature Communications, vol. 11, no. 1, 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 Ctr

AU - Shah, Sonia

AU - Henry, Albert

AU - Roselli, Carolina

AU - Lin, Honghuang

AU - Sveinbjornsson, Gardar

AU - Fatemifar, Ghazaleh

AU - Hedman, Asa 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 - Arnlov, 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 - Doerr, Marcus

AU - Dudley, Samuel C.

AU - Dunn, Michael E.

AU - Engstrom, Gunnar

AU - Esko, Tonu

AU - Felix, Stephan B.

AU - Finan, Chris

AU - Ford, Ian

AU - Ghanbari, Mohsen

AU - Ghasemi, Sahar

AU - Giedraitis, Vilmantas

AU - Giulianini, Franco

AU - Gottdiener, John S.

AU - van der Harst, Pim

AU - Voors, Adriaan A.

AU - Zhao, Jing Hua

AU - Asselbergs, Folkert W.

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 - RISK

KW - EPIDEMIOLOGY

KW - METAANALYSIS

KW - DISEASE

KW - LOCI

KW - HYPERTENSION

KW - IMPUTATION

KW - RESOURCE

KW - CATALOG

KW - OBESITY

U2 - 10.1038/s41467-019-13690-5

DO - 10.1038/s41467-019-13690-5

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 163

ER -

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

Abstract

Keywords

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