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. 2025 Jul 15.
doi: 10.1007/s00213-025-06851-6. Online ahead of print.

Branched-chain amino acids and risk of major depressive disorder: a Mendelian randomization and colocalization study

Xiang Li  1   2   3 , Jianyi Wang  4
Affiliations

Branched-chain amino acids and risk of major depressive disorder: a Mendelian randomization and colocalization study

Xiang Li et al. Psychopharmacology (Berl). .

Abstract

Aims: Depression is associated with numerous metabolic pathway abnormalities, and several studies have suggested a link between depression and branched chain amino acids (BCAAs) metabolic disorders. However, the precise causality and direction remain inconclusive. Consequently, this study aims to ascertain the relationship between the risk of depression and BCAAs levels using two-sample Mendelian randomization (MR) analysis.

Materials and methods: Single nucleotide polymorphisms associated with the BCAAs were extracted from the IEU OpenGWAS. Pooled level data for major depressive disorder (MDD) was obtained from the Psychiatric Genomics Consortium. We performed genome-wide linkage disequilibrium score regression, MR analyses, and colocalization analyses using summary genome-wide association study data across European population to probe genetic causality between BCAAs and MDD.

Results: Our results showed a causal effect of MDD risk on the increasing valine levels (IVW OR = 1.043, 95% CI = 1.006-1.082, P = 0.024) and a genetic correlation between MDD and valine. However, leucine, isoleucine, and total BCAAs were not causally associated with the risk of MDD (P > 0.05). The sensitivity analyses indicated that there was no heterogeneity or horizontal pleiotropy in our findings. The linkage disequilibrium score regression demonstrated significant evidence of shared genetic architecture between MDD and valine, with the genetic correlation estimated to be 0.112 (P = 0.002). Colocalization analysis did not provide any evidence of a shared causal variant between MDD and valine.

Conclusions: It was revealed that valine metabolism may be significantly affected by depression through a two-sample MR analysis, while no significant connection was identified between other branched-chain amino acids and depression. This result provided new insights into the metabolic processes involved in depression.

Keywords: Branched-chain amino acids; Genome-wide association study; Major depressive disorder; Mendelian randomization; Valine.

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Conflict of interest statement

Declarations. Ethical approval: Not applicable. Consent to participate: Not applicable. Consent to publish: Not applicable. Competing interests: All authors declare no conflicts of interest.

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