Causal association between lipid profile and mental disorders: evidence from a bidirectional Mendelian randomization...

Observational studies have indicated interplay between lipid profiles and mental disorders, but genetic causal evidence remains limited. This study aimed to assess bidirectional causal links between lipid profiles and five major mental disorders using Mendelian randomization (MR) analysis.

We performed a bidirectional two-sample MR analysis utilizing genome-wide association study (GWAS) summary statistics from European populations. Genetic instruments were selected for five psychiatric disorders (major depressive disorder (MDD), anxiety, attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BIP), and schizophrenia (SCZ)) and six lipid traits: triglycerides (TG), total cholesterol (TC), high-/low-density lipoprotein cholesterol (HDL/LDL) and apolipoproteins (Apo A-1, Apo B). The inverse-variance weighted (IVW) method served as the primary analytical approach, complemented by MR-Egger regression to evaluate horizontal pleiotropy.

Forward MR analysis suggested a significant causal relationship between LDL and MDD (p_(MDD) < 0.001, OR (95%CI) = 0.888 (0.833-0.946)), TG and anxiety (p_(anxiety) = 0.016, OR (95%CI) = 1.057(1.010-1.105)). Reverse MR analysis indicated that genetic liability to MDD ( p = 0.017, OR (95%CI) = 1.096(1.016-1.182), and ADHD ( p = 0.009, OR (95%CI) = 1.039( 1.009-1.069)) elevated TG levels, anxiety disorders increased HDL (p = 0.003, OR (95%CI) = 1.288( 1.029-1.520)), LDL (p = 0.001,OR (95%CI) = 1.176(1.066-1.298)), Apo A-1 (p = 0.012,OR(95%CI) = 1.306(1.060-1.609)), and Apo B (p = 0.007,OR(95%CI) = 1.134(1.036-1.241)), whereas SCZ was inversely correlated with lipid profiles. No causal relationships were observed for bipolar disorder.

These findings suggest that genetically predicted TG levels may influence anxiety risk, while genetic predisposition to MDD and ADHD may contribute to dyslipidemia. Our study provides genetic evidence supporting a potential causal interplay between lipid metabolism and mental disorders, highlighting the need for interdisciplinary care and personalized monitoring to address psycho-metabolic comorbidities.