publications

2025

1. 

   Immuno-Metabolic Pathways: Investigating Mediators of Major Depressive Disorder and Atherosclerotic Cardiovascular Disease Comorbidity

   Angela Koloi, Nabila P.R. Siregar, Rick Quax, and 7 more authors

   Biological Psychiatry Global Open Science, 2025

   Abs DOI

   Background: Major depressive disorder (MDD) and cardiovascular diseases (CVD) often co-occur whereby comorbidity results in poorer clinical outcomes, presumably due to shared immune-metabolic pathways. Identifying shared biomarkers for MDD-CVD comorbidity may provide targets for prevention or treatment. Methods: Using data from the Netherlands Study of Depression and Anxiety (NESDA: N=2,256, 66.3% female, mean age 41.75 ± 13.11 years), validated with the UK Biobank data (UKB, N=35,668, 56.14% female, mean age 63.95 ± 7.74 years), this study aimed to identify (i) biomarkers, closely associated with current MDD, and (ii) longitudinal pathways linking MDD and atherosclerotic CVD. Plasma metabolites (NMR, Nightingale) and inflammatory markers were used as exposures within a Machine Learning framework. Influential biomarkers were integrated into a temporal network analysis linking MDD to subsequent CVD, exploring longitudinal pathways through Causal Discovery, validated by sensitivity analysis and centrality assessment. External validation included mediation and regression analysis adjusting for covariates. Results: Network analysis identified stable direct paths from MDD to CVD via TNF-α, tyrosine, and fatty acids, and indirect paths via acetate, HDL diameter, IL-6, alpha-1-acid glycoprotein (AGP), hs-CRP, and LDL triglycerides. Among these, acetate, tyrosine, AGP, and HDL diameter potentially mediate the MDD-CVD connection, as these were identified as key nodes within the network. UKB validation confirmed HDL diameter (β = 0.004) and AGP (β = 0.003) as significant depression-CVD mediators (both p < .001), after adjusting for age, sex, deprivation index, alcohol consumption, smoking status, physical activity, and BMI. Conclusions: These analyses identified biomarkers shared in MDD and CVD and may drive comorbid pathology risk.