We present the results of the largest genome wide association study (GWAS) performed so far in dilated cardiomyopathy (DCM), a leading cause of systolic heart failure and cardiovascular death, with 2,719 cases and 4,440 controls in the discovery population. We identified and replicated two new DCM-associated loci, one on chromosome 3p25.1 (lead SNP rs62232870, p = 8.7 x 10-11 and 7.7 x 10-4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 x 10-8 and 1.4 x 10-3 in the discovery and replication step, respectively) while confirming two previously identified DCM loci on chromosome 10 and 1, BAG3 and HSPB7. The genetic risk score constructed from the number of lead risk-alleles at these four DCM loci revealed that individuals with 8 risk-alleles were at a 27% increased risk of DCM compared to individuals with 5 risk alleles (median of the referral population). We estimated the genome wide heritability at 31% +/- 8%. In silico annotation and functional 4C-sequencing analysis on iPSC-derived cardiomyocytes strongly suggest SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine and beta-alanine transporter whose involvement in myocardial dysfunction and DCM is supported by recent observations in humans and mice. Although less easy to discriminate the better candidate at the 22q11.23 locus, SMARCB1 appears as the strongest one. This study provides both a better understanding of the genetic architecture of DCM and new knowledge on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective.

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