Abstract
Polygenic risk scores (PRS) are an increasingly available tool to refine risk prediction for cardiometabolic diseases1. Favorable lifestyle behaviors might offset increased polygenic risk, but whether frequency of depressed mood stratifies PRS-associated risk is unknown. Here, we calculated individual-level 3-million variant PRS for coronary artery disease (CAD), type 2 diabetes (T2D) and atrial fibrillation2 among 328,152 genotyped, individuals of European ancestry in the UK Biobank. After adjustment for clinical/lifestyle factors and PRS, low versus high frequency of depressed mood was associated with lower risks of incident CAD by 34%, T2D by 33% and atrial fibrillation by 20%. Frequency of depressed mood stratified risk for CAD and T2D across low (lowest quintile), intermediate (middle three quintiles) and high (highest quintile) PRS strata. Depression was associated more strongly with CAD in women compared with men (Pinteraction < 0.001). Overall, lower burden of depressed mood was independently associated with lower risk of CAD and T2D across the cardiometabolic polygenic risk spectrum.