Metabolic and inflammatory traits and depression: a Mendelian randomization study with late-adolescent population-based and clinical triangulation

Metabolic dysfunction and systemic inflammation have been associated with adolescent depression, but their causal relevance remains uncertain. We examined whether insulin resistance, proxied by the triglyceride-glucose (TyG) index, and high-sensitivity C-reactive protein (hs-CRP) show genetically proxied associations with major depressive disorder (MDD), and evaluated their observational relevance in late adolescents from the general population and in a clinical adolescent sample.

We performed bidirectional two-sample Mendelian randomization (MR) using genome-wide association study (GWAS) summary statistics for the TyG index, hs-CRP, body mass index (BMI), and MDD, with inverse-variance weighting as the primary method, supplemented by sensitivity and multivariable MR analyses. Observational corroboration was sought in 327 late adolescents aged 18-19 years from the pooled 2015-2016 and 2017-March 2020 pre-pandemic cycles of the National Health and Nutrition Examination Survey (NHANES) and in a retrospective cohort of 224 adolescents with depression and 200 frequency-matched controls.

Genetically predicted higher TyG index (odds ratio [OR] 1.08, 95% confidence interval [CI] 1.03-1.14, P = 0.001) and hs-CRP (OR 1.11, 95% CI 1.05-1.16, P<0.001) were associated with higher odds of MDD; reverse MR analyses did not show statistically significant associations. In the late-adolescent NHANES sample, each 1-SD higher TyG index (adjusted OR 1.28, 95% CI 1.01-1.63) and each 1-SD higher log-transformed hs-CRP (adjusted OR 1.33, 95% CI 1.03-1.71) were associated with higher odds of moderate-to-severe depressive symptoms (Patient Health Questionnaire-9 score ≥10). In the clinical cohort, the TyG index (adjusted OR 1.35, 95% CI 1.15-1.58) and hs-CRP >3.0 mg/L (adjusted OR 2.55, 95% CI 1.60-4.06) were associated with higher odds of depression. In a multiple-imputation sensitivity analysis retaining all 561 exposure/outcome-complete NHANES participants, both NHANES associations remained directionally consistent with the primary complete-case estimates.

Converging but methodologically distinct lines of evidence-genetic, population-based, and clinical-are directionally consistent with a contribution of insulin resistance and systemic inflammation to depression across adolescence and late adolescence. These findings support further prospective and interventional evaluation of metabolic-inflammatory pathways rather than immediate clinical translation.