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

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posted on 07.05.2020, 10:21 by S Shah, A Henry, C Roselli, H Lin, G Sveinbjörnsson, G Fatemifar, ÅK Hedman, JB Wilk, MP Morley, MD Chaffin, A Helgadottir, N Verweij, A Dehghan, P Almgren, C Andersson, KG Aragam, J Ärnlöv, JD Backman, ML Biggs, HL Bloom, J Brandimarto, MR Brown, L Buckbinder, DJ Carey, DI Chasman, X Chen, J Chung, W Chutkow, JP Cook, GE Delgado, S Denaxas, AS Doney, M Dörr, SC Dudley, ME Dunn, G Engström, T Esko, SB Felix, C Finan, I Ford, M Ghanbari, S Ghasemi, V Giedraitis, F Giulianini, JS Gottdiener, S Gross, DF Guðbjartsson, R Gutmann, CM Haggerty, P van der Harst, CL Hyde, E Ingelsson, JW Jukema, M Kavousi, KT Khaw, ME Kleber, L Køber, A Koekemoer, C Langenberg, L Lind, CM Lindgren, B London, LA Lotta, RC Lovering, J Luan, P Magnusson, A Mahajan, KB Margulies, W März, O Melander, IR Mordi, T Morgan, AD Morris, AP Morris, AC Morrison, MW Nagle, CP Nelson, A Niessner, T Niiranen, ML O’Donoghue, AT Owens, CNA Palmer, HM Parry, M Perola, E Portilla-Fernandez, BM Psaty, G Abecasis, J Backman, X Bai, S Balasubramanian, N Banerjee, A Baras, L Barnard, C Beechert, A Blumenfeld, M Cantor, Y Chai, G Coppola
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.

History

Citation

Nature Communications, 2020, 11:163

Author affiliation

College of Life Sciences

Version

VoR (Version of Record)

Published in

Nature Communications

Volume

11

Issue

1

Pagination

163

Publisher

Nature Research

eissn

2041-1723

Acceptance date

18/11/2019

Copyright date

2020

Publisher version

https://www.nature.com/articles/s41467-019-13690-5#Abs1

Language

eng