Polygenic risk of cardiovascular disease manifests in cardiac structure and function

Cardiovascular diseases (CVDs) are highly heritable, but pathogenesis at the organ and physiological level is still poorly defined. Polygenic risk scores (PRSs), which estimate individual genetic susceptibility to a disease, may allow for the identification of associated abnormal organ structures. Ultimately, identifying where cardiovascular polygenic risk manifests can guide early interventions, shape mechanistic hypotheses, and motivate prevention trials for cardiac remodelling. This study investigated the association between PRSs for five common CVDs [heart failure (HF), coronary artery disease (CAD), atrial fibrillation (AF), abdominal aortic aneurysm (AAA) and ischaemic stroke (IS)] and 28 imaging-derived phenotypes (IDPs) from cardiac magnetic resonance imaging of ~62,000 participants in UK Biobank. To investigate the cardiac features associated with elevated polygenic risk of CVDs, we tested CVD PRSs against cardiac IDPs and identified 97 significant associations (FDR [≤] 0.05). We further identified 32 significant putative mediators between CVD PRSs and incident disease events, revealing that across CVDs, polygenic risk manifested as distinct patterns in cardiac structures. HF implicated all cardiac chambers, including left ventricular and left atrial dysfunction alongside enlarged aorta. AF was characterised by biatrial enlargement and reduced ejection fractions, most prominently in the left atrium but also involving left ventricular wall thickness. IS exhibited left ventricular hypertrophy and left atrial dysfunction, while CAD predominantly involved left ventricular hypertrophy. AAA was primarily characterised by enlarged descending aorta. Overall, cardiac IDPs mediated a substantial proportion of polygenic risk for CVDs, in particular for HF. Taken together, our results show that cardiac structure and function lie on the pathway between polygenic risk and cardiovascular events.