Causality of multiple serum metabolites on emotional lability: A two-sample Mendelian randomization study

Background: Emotional lability (EL)-a transdiagnostic feature characterized by rapid emotional shifts-contributes significantly to functional impairment across psychiatric disorders, such as depression, bipolar disorder, and schizophrenia. Despite its clinical significance, its etiology remains poorly understood, hindering effective screening and interventions. Growing evidence suggests that metabolic alterations may play a crucial role in the pathophysiology of psychiatric disorders. Methods: A comprehensive Mendelian randomization (MR) design incorporated summary-level data from extensive genome-wide association studies (GWAS) on serum metabolites (8299 European participants) and EL (3268 European samples) to investigate causal associations between genetically determined metabolite levels and EL. Assumptions of instrumental variables, heterogeneity, horizontal pleiotropy, and directionality were assessed alongside sensitivity analyses. Results: Out of 1400 metabolites and ratios analyzed, 30 metabolites demonstrated causal associations with an increased risk of EL based on the inverse-variance weighted method. Sensitivity analyses identified three potential causal metabolites: hydrocinnamate (OR: 1.277, CI: 1.071-1.522, P = 0.0063), which is associated with an increased risk, while glycolithocholate (OR: 0.779, CI: 0.667-0.911, P = 0.0017) and 3(3-hydroxy-5-cholenoic acid (OR: 0.857, CI: 0.756-0.971, P = 0.015) are associated with a decreased risk. Conclusion: This MR study supports a causal link between hydrocinnamate, glycolithocholate, and 3(3-hydroxy-5cholenoic acid levels and the incidence of EL, offering potential metabolic biomarkers and therapeutic targets for EL in psychiatric disorders.