Mendelian Randomization Supports a Causal Effect of Depression on Cardiovascular Disease as the Main Source of Their Comorbidity

Depression and manifestations of cardiovascular disease (CVD), including coronary artery disease (CAD), myocardial infarction (MI), ischemic stroke, heart failure, and atrial fibrillation, are strongly comorbid.1 Given their high prevalence and the many years lost to disability caused, establishing the causality underlying their comorbidity is of huge public health value. This is not a simple mission. Apart from chance, which is nonnegligible with 2 highly prevalent conditions, several mechanisms could underlie the co-occurrence of depression and CVD, ranging from biological (inflammatory processes, dysfunction in the hypothalamic-pituitary-adrenal and autonomic nervous systems, and endothelial and platelet dysfunction) and behavioral mechanisms (physical inactivity, poor eating habits, smoking, and drinking) to a shared genetic vulnerability or chronic stress linked to socioeconomic status, both of which could independently affect the risk of developing depression and CVD. Of note, these mechanisms are not mutually exclusive, and the depression-CVD comorbidity is likely a composite of all of them. The exact mixture may differ across people and possibly be symptom specific.2.