Mendelian-Randomization Study Reveals Causal Relationships Between Blood Metabolites and Psychiatric Disorders

Background and Hypothesis Metabolic dysregulation has been widely observed in psychiatric disorders. However, the causal relationships between metabolites and psychiatric disorders remain largely unknown. Study Design Here, we conducted bidirectional Mendelian randomization (MR) analyses to systematically investigate causal relationships between 8 psychiatric disorders (including attention deficit hyperactivity disorder (ADHD), anorexia nervosa (AN), anxiety, bipolar disorder (BIP), depression, posttraumatic stress disorder (PTSD), insomnia, and schizophrenia (SCZ)) and 1139 blood metabolites (including 823 metabolite levels and 316 metabolite ratios). Study Results In forward MR, we identified 34, 21, 56, and 1 metabolites that are associated with BIP, SCZ, depression, and PTSD, respectively. Notably, several metabolites are associated with the risk of multiple psychiatric disorders. For instance, N2,N2-dimethylguanosine, 1,2-dipalmitoyl-gpc (16:0/16:0), and phosphatidylcholine acyl-alkyl C38:4 were negatively associated with the risk of SCZ and BIP. In reverse MR analyses, we explored the causal effects of psychiatric disorders on metabolites, and found that blood metabolites are also influenced by psychiatric disorders. For example, depression significantly affected 21 metabolite levels, including positively associated with 21-hydroxypregnenolone disulfate, and negatively associated with carotenoid. Conclusions Our findings not only uncover the causal relationships between metabolites and psychiatric disorders, but also provide potential therapeutic targets for the prevention and treatment of these psychiatric disorders.