Genome-wide association analysis reveals insights into the molecular etiology underlying dilated cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a clinical disorder characterised by reduced contractility of the heart muscle that is not explained by coronary artery disease or abnormal haemodynamic loading. Although Mendelian disease is well described, clinical testing yields a genetic cause in a minority of patients. The role of complex inheritance is emerging, however the common genetic architecture is relatively unexplored. To improve our understanding of the genetic basis of DCM, we perform a genome-wide association study (GWAS) meta-analysis comprising 14,255 DCM cases and 1,199,156 controls, and a multi-trait GWAS incorporating correlated cardiac magnetic resonance imaging traits of 36,203 participants. We identify 80 genetic susceptibility loci and prioritize 61 putative effector genes for DCM by synthesizing evidence from 8 gene prioritization strategies. Rare variant association testing identifies genes associated with DCM, includingMAP3K7, NEDD4L, andSSPN. Through integration with single-nuclei transcriptomics from 52 end-stage DCM patients and 18 controls, we identify cellular states, biological pathways, and intercellular communications driving DCM pathogenesis. Finally, we demonstrate that a polygenic score predicts DCM in the general population and modulates the penetrance of rare pathogenic and likely pathogenic variants in DCM-causing genes. Our findings may inform the design of novel clinical genetic testing strategies incorporating polygenic background and the genes and pathways identified may inform the development of targeted therapeutics.

Genetic and phenotypic architecture of human myocardial trabeculation

“…We used LocusZoom, eQTLs, and transcriptome-wide association study to prioritise genes at each locus. The identified associations include loci of definitive evidence cardiomyopathy-associated genes ( TNNT2, TTN, PLN ) and colocalise with recent HCM (e.g., TBX3, STRN, MTSS1 26 ), DCM (e.g., PKD1, STRN, MITF, CDKN1A 27 ), and heart failure GWAS 28 . For sensitivity analyses, we removed any individuals in the UK Biobank who had a diagnosis of any cardiomyopathy or heart failure.…”

“…Hyper-and hypo-trabeculation were deemed > or < 1.5 standard deviations from the mean. Mendelian randomization was assessed using GWAS Summary statistics from published literature [26][27][28] with mean global FD using the R packages TwoSampleMR and MVMR. Exposure variants were included if GWAS significant (P<5x10 −8 ).…”

“…Genes of independent loci were prioritized through LocusZoom, eQTLs from GTEx v8, and transcriptome-wide association study (TWAS). TWAS with S-MultiXcan 53 was completed using the GWAS summary statistics from GTEx V8 which identified 128 cardiac-specific (left ventricle and atrial appendage) genes and 336 genes from all tissues that significantly associated with trabeculation after correction for the number of tested genes ( Table S11-S12 ) 26,27 . Phenotype associations through GWAS catalog, Phenoscanner, and PheWEB, were assessed ( Table S5, Table S9 ), and resulting genes were analysed by gene ontology (GO) resource enrichment analysis using Panther ( Table S13 ).…”

The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum

“…Zheng et al ( 2023) conducted the largest DCM GWAS to date comprising over 14,255 DCM cases from the HERMES consortium [61]. Through gene prioritisation strategies such as pathway enrichment analysis and utilisation of genetically correlated CMR traits from UK biobank, 80 loci associated with DCM were discovered.…”