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

Sophie Garnier, Magdalena Harakalova, Stefan Weiss, Michal Mokry, Vera Regitz-Zagrosek, Christian Hengstenberg, Thomas P. Cappola, Richard Isnard, Eloisa Arbustini, Stuart A. Cook, Jessica van Setten, Jorg J.A. Calis, Hakon Hakonarson, Michael P. Morley, Klaus Stark, Sanjay K. Prasad, Jin Li, Declan P. O'Regan, Maurizia Grasso, Martina Müller-NurasyidThomas Meitinger, Jean Philippe Empana, Konstantin Strauch, Melanie Waldenberger, Kenneth B. Marguiles, Christine E. Seidman, Georgios Kararigas, Benjamin Meder, Jan Haas, Pierre Boutouyrie, Patrick Lacolley, Xavier Jouven, Jeanette Erdmann, Stefan Blankenberg, Thomas Wichter, Volker Ruppert, Luigi Tavazzi, Olivier Dubourg, Gérard Roizes, Richard Dorent, Pascal de Groote, Laurent Fauchier, Jean Noël Trochu, Jean François Aupetit, Zofia T. Bilinska, Marine Germain, Uwe Völker, Daiane Hemerich, Ibticem Raji, Delphine Bacq-Daian

Research output: Contribution to journalArticlepeer-review

Abstract

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 × 10-11 and 7.7 × 10-4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10-8 and 1.4 × 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.

Original languageEnglish
Pages (from-to)2000-2011
Number of pages12
JournalEuropean Heart Journal
Volume42
Issue number20
DOIs
Publication statusPublished - May 21 2021

Keywords

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

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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