Distinct genomic signatures and modifiable risk factors underly the comorbidity between major depressive disorder and cardiovascular disease

Major depressive disorder (MDD) and cardiovascular disease (CVD) are often comorbid, resulting in excess morbidity and mortality. Using genetic data, this study elucidates biological mechanisms, key risk factors, and causal pathways underlying the comorbidity. We show that CVDs share a large proportion of their genetic risk factors with MDD. Multivariate genome-wide association analysis of the shared genetic liability between MDD and CVD revealed seven novel loci and distinct patterns of tissue and brain cell-type enrichments, suggesting a role for the thalamus. Part of the genetic overlap was explained by shared inflammatory, metabolic, and psychosocial risk factors. Finally, we found support for causal effects of genetic liability to MDD on CVD risk, but not vice versa, and demonstrated that the causal effects are partly explained by metabolic and psychosocial factors. The distinct signature of MDD-CVD comorbidity aligns with the idea of an immunometabolic sub-type of MDD more strongly associated with CVD than overall MDD. In summary, we identify plausible biological mechanisms underlying MDD-CVD comorbidity, as well as key modifiable risk factors for prevention of CVD in individuals with MDD.