Large-scale genetic and multi-omics analyses identify molecular pathways underlying dilated cardiomyopathy

Abstract Background Dilated cardiomyopathy (DCM) is a heart muscle disease that represents a major public health burden. While both common and rare genetic variants are known to affect DCM risk, previous genome-wide association studies (GWAS) have yielded only few loci and the molecular pathways underlying DCM remain largely unknown. Purpose We aimed to discover novel genetic loci for DCM by combining data from biobank and case-control studies, and by combining GWAS with multi-trait analyses. We also pursued multi-omics Mendelian randomization to nominate novel molecular pathways underlying DCM. Methods and results We first performed a GWAS of ICD-code defined DCM (N=1472 cases) from two large biobank datasets (UK Biobank and Mass General Brigham Biobank), and found good genetic correlation (rg=0.82, SE=0.22) and similar heritability estimates (h2=0.12, SE=0.03 vs. h2=0.14, SE=0.03) when compared with a previously published GWAS of recruited DCM cases. In a large meta-analysis across case-control and biobank datasets (N=4191 cases), we identified 10 loci significantly associated with DCM. We then integrated this novel meta-analysis into a multi-trait GWAS (MTAG) with MRI-derived left ventricular traits from the UK Biobank (LVEF and LVESV; N=36083), which yielded 44 lead variants at 36 significant loci. Novel loci overlap reported Mendelian cardiomyopathy genes (ACTN2, OBSCN, MYH7B), support previous mechanistic findings (HSPB8; heat shock protein family), and include genomic regions also arising from a recent GWAS of hypertrophic cardiomyopathy (notably, SVIL). We then performed Mendelian randomization analyses on the MTAG GWAS, using genetic instruments from published multi-omics datasets. Mendelian randomisation of the blood metabolome suggests potential causal roles for metabolites, notably those involved in the pentose phosphate pathway (ribitol; β=0.25, SE=0.04) and glycemic excursion (1,5-anhydroglucitol; β=0.08, SE=0.02). Analyses of the blood proteome suggest potential causal roles for several serum proteins, including proteins involved in redox balance (glutathione synthetase; β=-0.34, SE=0.05), mTORC1 signalling (LAMTOR3; β=0.08, SE=0.01), and the pentose phosphate pathway (G6PE; β=0.09, SE=0.02). Conclusion Our analyses link several new genomic regions with DCM, and implicate redox disbalance and alternative usage of (gluco)metabolic pathways as putative causal mechanisms of disease. Future functional studies could determine whether these represent actionable findings.

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