Unravelling the role of alanine in mental disorders: a Mendelian randomisation study

Alanine, commonly found in meaty foods and popular as a sports supplement, has interactions with neurotransmitters and brain energy supply, but its impact on mental health remains uncertain. This two-sample Mendelian randomisation (MR) study aimed to investigate causal associations of plasma alanine with major mental disorders-depression, bipolar disorder, schizophrenia, anxiety, and attention-deficit hyperactivity disorder (ADHD) and to further explore sex-specific associations using available data, considering potential sex disparity. We utilised genetic variants from the UK Biobank to predict plasma alanine (N = 115,074) and obtained their genetic associations with depression (N _cases = 194,180 and N _controls = 521,663), bipolar disorder (N _cases = 46,418 and N _controls = 563,769), schizophrenia (N _cases = 52,017 and N _controls = 75,889), anxiety (N _cases = 19,529 and N _controls = 212,855), and ADHD (N _cases = 46,418 and N _controls = 402,606) from genome-wide association studies (GWASs) in the Psychiatric Genomics Consortium (PGC) and FinnGen Biobank. MR estimates were primarily derived using the inverse variance weighted (IVW) method, with weighted median, MR-Egger, and MR-RAPS applied as sensitivity analyses. MR-PRESSO was used to detect pleiotropy and outliers. Genetically predicted alanine was nominally associated with a lower risk of schizophrenia overall (OR 0.88, 95% CI: 0.79-0.99) and in males (OR 0.88, 95% CI: 0.77-0.99), which were not significant after multiple testing. No association was detected in females (OR 0.92, 95% CI: 0.80-1.05). There was no evidence linking plasma alanine to depression, bipolar disorder, anxiety, or ADHD. These findings suggest that alanine might have an inverse association with schizophrenia, which may be more evident in males, but has no psychiatric side effects on other mental disorders. Replication in larger studies is warranted.