Abstract
CONTEXT: Observational studies indicated obesity and glutamatergic dysfunction as potential risk factors of depression, and reported disturbance of glutamine metabolism in obese state. However, it remains unclear whether the interrelationships between obesity, glutamine, and depression are causal. OBJECTIVE: We conducted 2-sample bidirectional mendelian randomization (MR) analyses to explore the causalities between circulating glutamine levels, specific depressive symptoms, major depressive disorder (MDD), and body mass index (BMI). METHODS: Univariable MR, multivariable MR (MVMR), and linkage disequilibrium score regression (LDSR) analyses were performed. RESULTS: Genetic downregulation of glutamine was causally associated with MDD, anhedonia, tiredness, and depressed mood at the false discovery rate (FDR)-controlled significance level (estimate, -0.036 ∼ -0.013; P = .005 to P = .050). Elevated BMI was causally linked to lower glutamine level (estimate, -0.103; P = .037), as well as more severe depressed mood, tiredness, and anhedonia (estimate, 0.017 ∼ 0.050; P < .001 to P = .040). In MVMR analysis, BMI was causally related to depressed mood dependently of glutamine levels. Conversely, it showed limited evidence supporting causal effects of depression on glutamine levels or BMI, except a causal association of tiredness with elevated BMI (estimate, 0.309; P = .003). LDSR estimates were directionally consistent with MR results. CONCLUSION: The present study reported that higher BMI was causally associated with lower glutamine levels. Both obesity and downregulation of glutamine were causally linked to depression.