Shared genetic pathways contribute to risk of hypertrophic and dilated cardiomyopathies with opposite directions of effect

Abstract

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young otherwise healthy individuals. We conducted genome-wide association studies (GWAS) and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases), and nine left ventricular (LV) traits in 19,260 UK Biobank participants with structurally normal hearts. We identified 16 loci associated with HCM, 13 with DCM, and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased contractility with HCM risk. A polygenic risk score (PRS) explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that PRS may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

“…Other types of genetic variation that to date have received less investigation in DCM, including promoter variants, common variants, or structural variants exceeding in size those able to be detected by next generation sequencing, also may be relevant to define DCM genetic cause. The recent use of larger DCM cohorts has revealed common variants that modulate the DCM rare variant phenotype studied here, 43 which underscores the utility and need of assembling even larger cohorts of patients and families with DCM for study. Furthermore, a majority of contemporary gene-disease association studies represent populations of primarily European ancestry.…”

Sex Differences in Hypertrophic Cardiomyopathy: Interaction With Genetics and Environment

“…In some cases, patients remain gene-elusive despite evidence for heritability, and there is growing awareness that a proportion of HCM is due to a complex interplay between genetic and environmental factors. Indeed, results from two recent genome-wide association studies in large HCM cohorts suggest that common variants account for an important proportion of heritability (SNP heritability ~ 30%), suggesting a role for genetic and non-genetic factors in penetrance and expression [6,7].…”

The TRIB3 R84 variant is associated with increased left ventricular mass in a sample of 2426 White individuals

“…Unfortunately, neither the TRIB3 Q84R polymorphism, nor any other SNP in good linkage disequilibrium with it, has been included in the arrays used in the publicly available genome-wide association studies (GWAS) for left ventricular mass, thus precluding the possibility of performing in silico analyses. However, in a recent meta-analysis of three GWAS including hypertrophic cardiomyopathy cases of European ancestry from the Netherlands, the United Kingdom and Canada, SNP rs6115789, a good proxy of the TRIB3 Q84R polymorphism, was found to be associated with hypertrophic cardiomyopathy in Dutch individuals ( P = 6 × 10 –4 ), indicating the need for further studies to address the role of the TRIB3 Q84R polymorphism in LVM [ 33 ].The current study was therefore undertaken to assess the impact of Q84R TRIB3 variant on LVM in a large group of individuals participating in the CATAMERI study, an ongoing observational study recruiting adult subjects with one or more cardiometabolic risk factors who underwent a complete clinical characterization including standard Doppler echocardiography [ 34 ].…”