Exome-wide association study reveals novel susceptibility genes to sporadic dilated cardiomyopathy

Aims Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. Methods and results Overall, 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value  TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3 . In silico fine mapping and protein interaction experiment with BAG3 identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF  TTN variants only ( P  = 0.0085). All candidate genes at associated loci but one ( SLC39A8 ) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. These candidate genes also share structural and functional roles suggesting sarcomeric maintenance as an important feature protecting against DCM. Conclusion We identified eight loci independently associated with sporadic DCM. Overlap between susceptibility gene and familial DCM causing gene suggests a continuum of effect size, or penetrance, in DCM associated molecular variants. The functions of the best candidate genes at these loci also suggest that proteostasis regulation might play a role in DCM pathophysiology.