Triglyceride-glucose index, genetic predisposition, and incident depression: a prospective cohort study from the UK...

The triglyceride-glucose (TyG) index, a surrogate marker for insulin resistance, has been associated with depressive symptoms, but findings are inconsistent and predominantly based on cross-sectional studies. This study investigated whether the TyG index is associated with incident depression independent of genetic predisposition and explored potential risk factors underlying this association.

A total of 335,586 UK Biobank participants without baseline depression were included. Incident depression cases were extracted by linking electronic health records. Polygenic risk scores quantified genetic predisposition. Cox proportional hazards models examined the associations. We further evaluated the contribution of socioeconomic status (education, employment, and Townsend Deprivation Index), lifestyle factors (smoking, alcohol consumption, physical activity, and sleep duration), biological indicators (body mass index and total cholesterol), and health conditions (hypertension, diabetes, and cardiovascular disease). No preregistered protocol was used.

During a mean follow-up of 13.1 years, 14,096 (4.2%) individuals developed depression. Compared with the lowest TyG quartile (Q1), the fully adjusted hazard ratios (95% confidence intervals) for Q2, Q3, and Q4 were 1.051 (1.000-1.104), 1.078 (1.025-1.134), and 1.144 (1.086-1.206), respectively (P for trend <0.001). Per standard deviation increment in the TyG index was associated with a 5.9% (3.9%-7.8%) higher risk of depression. Individuals with both high TyG levels and high genetic predisposition had the highest risk, although no significant interaction was observed. All adjusted risk factors appeared to attenuate 63.9% of the association.

A higher TyG index was associated with increased risk of incident depression, independent of genetic predisposition.