Mapping the genetic landscape of eight common cardiovascular diseases

Abstract

Cardiovascular diseases (CVDs) frequently co-occur, yet the shared genetic basis of cardiovascular multimorbidity remains unclear. We analysed common- and rare-variant genetic overlap across eight major CVDs using genome-wide and exome-wide association data from [~]1.7 million individuals in European and East Asian biobanks. Fifteen CVD pairs showed significant genetic correlations, with shared common-variant covariance explaining a modest proportion of phenotypic comorbidity. Genomic structural equation modelling identified three latent genetic clusters, while pleiotropic loci and genes frequently spanned cluster boundaries. Prioritised genes converged on atherosclerosis-related processes, myocardial structural and electrical programmes, and vascular-wall biology. In conditional analyses, body composition and metabolic traits consistently attenuated shared genetic liability, whereas circulating biomarkers showed smaller effects. For adequately powered traits, common-variant architecture was broadly similar between European and East Asian ancestries. These results define a shared genetic framework for cardiovascular multimorbidity centred on systemic risk factors and vascular biology.