Shared Genetic Architecture Contributes to Risk of Major Cardiovascular Diseases

Abstract

Abstract The extensive co-occurrence of cardiovascular diseases (CVDs), as evidenced by epidemiological studies, aligns with positive genetic correlations identified in comprehensive genetic investigations. However, the precise nature and mechanisms governing these multifaceted effects remain elusive. By assessing genome-wide and local genetic correlations, polygenic overlaps, and causal connections, we aimed to shed light on common genetic underpinnings among major CVDs. Employing a multi-trait analysis, we pursued diverse strategies to unveil shared genetic elements. These encompassed genomic loci, single-nucleotide polymorphisms (SNPs), genes, biological pathways, functional categories, and protein targets with pleiotropic implications. Our study confirmed elevated genetic resemblance across CVDs and pinpointed 40 genomic loci with pleiotropic influence across multiple CVDs. Notably, 11 of these loci presented consistent evidence from both Metasoft and HyPrColoc's multitrait colocalization analyses, displaying congruent directional effects. Examination of genes linked to these genomic loci unveiled robust associations with circulatory system development processes. Intriguingly, distinct patterns predominantly driven by atrial fibrillation, coronary artery disease, and venous thromboembolism underscored significant disparities between clinically-defined CVD classifications and underlying biological mechanisms. In summary, our findings provide invaluable insights into shared genetic mechanisms spanning CVDs. This knowledge holds potential to guide a biologically-informed restructuring of cardiovascular nosology and innovative therapeutic advancements.