TY - JOUR

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

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 - Ghanbari, Mohsen

AU - Ghasemi, Sahar

AU - Giedraitis, Vilmantas

AU - Giulianini, Franco

AU - Gottdiener, John S

AU - Køber, Lars

AU - Stender, Steen

AU - Torp-Pedersen, Christian

AU - Weeke, Peter E

AU - Regeneron Genetics Center

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.

U2 - 10.1038/s41467-019-13690-5

DO - 10.1038/s41467-019-13690-5

M3 - Journal article

VL - 11

SP - 163

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

ER -