Association of branched-chain amino acids with major depressive disorder: A bidirectional Mendelian randomization study

Background: Recent studies have linked branched-chain amino acids (BCAAs) metabolism with the risk of major depressive disorder (MDD). However, it is unclear whether associations of plasma BCAA levels with MDD are causal or driven by reverse causality. Methods: Mendelian randomization (MR) was used to investigate the causal association of genetically determined BCAA levels with the risk of MDD. The large genome-wide association study (GWAS) datasets on plasma BCAA levels (n = 115,051) were obtained from the UK Biobank. The summary GWAS dataset for MDD was obtained from the Psychiatric Genomics Consortium (n = 1,035,760). We applied the inverse variance-weighted (IVW) method to explore the causal relationships between BCAA levels and MDD, followed by multiple pleiotropy and heterogeneity tests. Results: Our results demonstrated that genetically determined circulating total BCAAs (odds ratio (OR): 1.05, 95 % confidence interval (CI): 1.01–1.10, P = 0.016), leucine (OR: 1.06, 95 % CI: 1.02–1.11, P = 7.22 × 10⁻³), and isoleucine (OR: 1.08, 95 % CI: 1.01–1.16, P = 0.032) levels were associated with an increased risk of MDD. There was suggestive evidence supporting the causal effect of valine levels on MDD (OR: 1.04, 95 % CI: 1.00–1.08, P = 0.075). Bidirectional MR analysis did not provide evidence of reverse causality. Conclusions: We report evidence supporting the causal role of BCAAs in the development of MDD. This study offers new insights into the mechanisms and treatment of MDD.