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Research article - Peer-reviewed, 2021

Genome-wide association analysis in dilated cardiomyopathy reveals two new players in systolic heart failure on chromosomes 3p25.1 and 22q11.23

Garnier, Sophie; Harakalova, Magdalena; Weiss, Stefan; Mokry, Michal; Regitz-Zagrosek, Vera; Hengstenberg, Christian; Cappola, Thomas P.; Isnard, Richard; Arbustini, Eloisa; Cook, Stuart A.; van Setten, Jessica; Calis, Jorg J. A.; Hakonarson, Hakon; Morley, Michael P.; Stark, Klaus; Prasad, Sanjay K.; Li, Jin; O'Regan, Declan P.; Grasso, Maurizia; Mueller-Nurasyid, Martina;
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Aims: Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure.Methods and results: We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 x 10(-11) and 7.7 x 10(-4) in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 x 10(-8) and 1.4 x 10(-3) in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene.Conclusion: This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.[GRAPHICS]


Dilated cardiomyopathy; Heart failure; GWAS; Imputation; 4C-sequencing; Genetic risk score

Published in

European Heart Journal
2021, Volume: 42, number: 20, pages: 2000-2011

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    Cardiac and Cardiovascular Systems

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