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

Abstract

SummaryWe 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 × 10−11 and 7.7 × 10−4 in the discovery and replication step, respectively) and the second on chromosome 22q11.23 (lead SNP rs7284877, p = 3.3 × 10−8 and 1.4 × 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.

Current State and Future of Polygenic Risk Scores in Cardiometabolic Disease: A Scoping Review

“…Five studies published a PRSs related to a heritable cardiomyopathy (Table 2). [17][18][19][20][21] Garnier et al 19 conducted the largest GWAS to date in dilated cardiomyopathy and derived an 8 SNP PRS that revealed a 3-fold increased risk of dilated cardiomyopathy.…”

Diagnosis and Risk Prediction of Dilated Cardiomyopathy in the Era of Big Data and Genomics

“…An explanation for the limited diagnostic yield of monogenetic causes and incomplete penetrance of DCM-associated variants is a common genetic variation [ 59 ]. To understand the relationship between these common genetic variants and DCM, researchers conducted several case-control genome-wide association studies (GWASs) and one exome-wide association study (EWAS) [ 60 , 61 , 62 , 63 ]. The three GWASs identified several loci including the following genes: HSPB7 , BAG3 , HCG22 , SLC6A6 , and SMARCB1 [ 60 , 61 , 63 ].…”

“…To understand the relationship between these common genetic variants and DCM, researchers conducted several case-control genome-wide association studies (GWASs) and one exome-wide association study (EWAS) [ 60 , 61 , 62 , 63 ]. The three GWASs identified several loci including the following genes: HSPB7 , BAG3 , HCG22 , SLC6A6 , and SMARCB1 [ 60 , 61 , 63 ]. The EWAS reported eight loci independently associated with sporadic DCM, five of which included genes that harbour rare DCM causing variants ( TTN , ALPK3 , BAG3 , FLNC , and FHOD3) [ 62 ].…”