Does genetic susceptibility to depression increase the risk of cardiometabolic diseases in adults?
There is a bidirectional genetic association between depression and cardiometabolic diseases, though the clinical relevance may be limited due to small effect sizes and high study heterogeneity.
Background: Depression is a risk factor for cardiometabolic diseases, but the extent to which this is attributable to genetic (rather than environmental) factors is unclear. Mendelian randomisation (MR) uses genetic variants to infer causality. We aimed to investigate the bidirectional association between respective genetic susceptibility to depression and cardiometabolic diseases. Methods: We conducted a systematic review and meta-analysis of MR studies (unidirectional or bidirectional) in adults that assessed associations between genetic variants related to depression and any cardiometabolic disease. A comprehensive literature search of MEDLINE, EMBASE, PsycINFO, CINAHL, Scopus, Web of Science, and Cochrane Library was performed to capture relevant articles published between database inception to June 20, 2024. This search was updated on April 23, 2025. Reference lists of included articles were manually searched for additional records. Articles published in English or translated into English were included. Primary outcomes of interest included cardiovascular diseases (six) and metabolic diseases (three). Contextually similar studies were pooled and sub-grouped based on population ancestry, study design, and outcome definition. A customised risk of bias tools for Mendelian randomisation was used to assess the risk of bias across five domains. Heterogeneity was assessed via I2 and tau-squared (τ2) statistics and publication bias was assessed via visual inspection of contour-enhanced funnel plots. This work is registered with PROSPERO, CRD42023460334. Findings: = 87%). Leave-one-out analyses showed that some studies altered the results more than the others. Interpretation: Our findings suggest that depression and cardiometabolic diseases are associated with each other. Though the observed effects are small and of limited immediate clinical relevance, our findings reflect the genetic component of the association separately to the behavioural and environmental influences. Treatment strategies identifying those at risk could benefit both diseases; however, high heterogeneity warrants cautious interpretation of our findings. Funding: None.
Jabeen et al. (Wed,) studied this question.