Morbidity-bridging metabolic pathways: linking early cardiovascular disease risk and depression symptoms using a multi-modal approach

Aims Prevalence of cardiovascular diseases (CVDs) and depression is rising globally. Their co-occurrence associates with poorer outcomes, potentially due to shared metabolic pathways. This study aimed to identify metabolic pathways linking depression symptoms and CVD risk factors. Methods and results Data from the Young Finns Study (YFS, n = 1,599, mean age 37 ± 5, 54% female) served as input for a network (mixed graphical models). Confirmatory analysis through covariate-adjusted regression was done with UK Biobank (UKB, n = 69,513, mean age 63 ± 7, 64% female). Mendelian randomization assessed causality using genome-wide association studies data. The study examined 52 plasma metabolites measured by nuclear magnetic resonance spectroscopy. Outcomes included depression symptoms (BDI in YFS, PHQ-9 in UKB) and CVD risk factors [systolic/diastolic blood pressure, carotid intima–media thickness (cIMT)]. Mendelian randomization inferred causal links between metabolites and depression or (intermediate markers of) CVD. Two bridge metabolites were identified: glucose linked to sleep pattern (P = 0.034); omega-3 fatty acids (FAs) linked to appetite change (P < 0.001); and both connected to cIMT (both P = 0.002). Mendelian randomization suggested glucose as causal in coronary artery disease (CAD) risk, while omega-3 FAs showed potential causal links to CAD, coronary artery calcification, and cIMT. Conclusion This study integrated three statistical techniques and identified two metabolic markers (glucose, omega-3 FAs) connecting depression and CVD on a symptom and risk factor level. The associations, established in a relatively young cohort, were replicated in a predominantly middle-aged cohort and emphasize both the generalizability of the findings across different populations and value of symptom-level analysis in depression and CVD comorbidity research.