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

Background Dilated cardiomyopathy (DCM) is a major cause of systolic heart failure and therefore a major public health issue. Purpose Our objective was to better understand the genetic bases of dilated cardiomyopathy. Methods We conducted a 1000G based genome-wide association study for 9,152,885 SNPs on 2,719 sporadic DCM cases and 4,440 controls of European origin followed by a replication step. We then sought for the most likely culprit genes at the new replicated loci through a dedicated strategy including in silico data mining (including tissue specific gene expressions, expression and methylation quantitative trait loci) as well as functional 4C-sequencing analysis on iPSC-derived cardiomyocytes ( Fig. 1 ). Results We identified two new DCM loci, on chromosome 3p25.1 (lead 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, respectively), while confirming two previously identified ones, BAG3 and HSPB7. A Genetic Risk Score was built from the number of risk allele at these four loci and revealed a 27% increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). At chr3p25, our selection strategy pinpointed SLC6A6 as the most likely culprit gene. SLC6A6 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, the same strategy strongly suggested SMARCB1 as the best candidate gene. Conclusion This study provides new insights in the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure, with the potential for a therapeutic perspective especially through taurine modulation.