Metabolic and inflammatory traits and depression: a Mendelian randomization study with late-adolescent population-based and clinical triangulation
- 1Department of Psychiatry, Ganzhou Hospital–Nanfang Hospital, Southern Medical University (Ganzhou People’s Hospital)
Abstract
Objective: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
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BibTeX
@article{wu2026metabolic,
title = {{Metabolic and inflammatory traits and depression: a Mendelian randomization study with late-adolescent population-based and clinical triangulation}},
author = {Yanping Wu and Zhenyu Xu and Daolin Wu},
journal = {Frontiers in Psychiatry},
year = {2026},
month = oct,
doi = {10.3389/fpsyt.2026.1935185},
url = {https://www.frontiersin.org/articles/10.3389/fpsyt.2026.1935185/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Metabolic and inflammatory traits and depression: a Mendelian randomization study with late-adolescent population-based and clinical triangulation
AU - Yanping Wu
AU - Zhenyu Xu
AU - Daolin Wu
PY - 2026
DA - 2026/10/16
JO - Frontiers in Psychiatry
DO - 10.3389/fpsyt.2026.1935185
UR - https://www.frontiersin.org/articles/10.3389/fpsyt.2026.1935185/full
AB - Objective: 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. Methods: 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. Results: 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. Conclusion: 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.
SN - 1664-0640
ER -