The causal effect of folate on major depressive disorder: Mendelian randomization, LDSC, and colocalization analysis

Dietary intervention is beneficial in reducing the risk of major depressive disorder (MDD). Nevertheless, whether the intake of macronutrients and vitamin B supplements is causally associated with MDD remains unclear. Univariate Mendelian randomization was performed to identify the causal effect of the relative intake of macronutrients (including fat, protein, and carbohydrates) and vitamin B (including vitamin B6, vitamin B12, and folate) on MDD in 338,111 individuals. Moreover, we further analyzed the genetic associations between the intake of macronutrients and vitamin B and the progression of MDD via linkage disequilibrium score regression and colocalization. Additionally, we explored the influence of DNA methylation caused by folate supplementation on the risk of MDD. Our univariate Mendelian randomization findings revealed that high folate levels were associated with a low risk of MDD (OR = 0.010, 95% CI: 0.001-0.184). Moreover, the relative intake of protein, fat, and carbohydrate, along with vitamin B6 and vitamin B12, was not associated with MDD. Linkage disequilibrium score regression revealed a genetic correlation between folate supplementation and MDD (rg = -0.470, P = .001). Colocalization analysis revealed that folate supplementation and MDD share a causal variant (rs115879259). Additionally, 3 folate-related CpG sites (cg03651886, cg03986574, and cg10664184) were causally associated with MDD progression. Our study provides evidence that folate supplementation decreases the risk of MDD.