A genome-wide association study identifies two loci associated with heart failure due to dilated cardiomyopathy

Eric Villard, Claire Perret, Françoise Gary, Carole Proust, Gilles Dilanian, Christian Hengstenberg, Volker Ruppert, Eloisa Arbustini, Thomas Wichter, Marine Germain, Olivier Dubourg, Luigi Tavazzi, Marie Claude Aumont, Pascal De Groote, Laurent Fauchier, Jean Noël Trochu, Pierre Gibelin, Jean François Aupetit, Klaus Stark, Jeanette ErdmannRoland Hetzer, Angharad M. Roberts, Paul J R Barton, Vera Regitz-Zagrosek, Cardiogenics Consortium, Uzma Aslam, Laëtitia Duboscq-Bidot, Matthias Meyborg, Bernhard Maisch, Hugo Madeira, Anders Waldenström, Enrique Galve, John G. Cleland, Richard Dorent, Gerard Roizes, Tanja Zeller, Stefan Blankenberg, Alison H. Goodall, Stuart Cook, David A. Tregouet, Laurence Tiret, Richard Isnard, Michel Komajda, Philippe Charron, François Cambien

Research output: Contribution to journalArticlepeer-review

Abstract

Aims Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved.We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM. Methods and results One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P <5.0 10-7), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease. Conclusion This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.

Original languageEnglish
Pages (from-to)1065-1076
Number of pages12
JournalEuropean Heart Journal
Volume32
Issue number9
DOIs
Publication statusPublished - May 2011

Keywords

  • BAG3
  • CLCNKA
  • Dilated cardiomyopathy
  • Genome wide association study
  • Heart failure
  • HSPB7

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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