Genetically predicted serum urate levels have no causal role on depression or other psychiatric disorders

Clinicians are advised caution in reducing serum urate for gout management due to observational associations with risk of neuropsychiatric diseases. We examined the causal effect of genetically predicted serum urate levels on the risk of major depressive disorder (MDD), anxiety, and related psychiatric disorders using two-sample Mendelian randomization (MR). We identified single-nucleotide polymorphisms (SNPs) associated with serum urate from a genome-wide association study (GWAS) of 110,347 European-descent individuals. The causal effect of serum urate on MDD was tested using summary data from a GWAS of 135,458 cases and 344,901 controls of European descent. MR was performed using random-effects inverse variance-weighted method and a series of sensitivity analyses. This approach was repeated using summary GWAS data for anxiety, bipolar disorder, post-traumatic stress disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, schizophrenia, and anorexia nervosa. We identified 30 SNPs associated with serum urate. Genetically predicted urate levels were not causally associated with risk of MDD (OR 0.98; 95% CI 0.94, 1.03), anxiety (OR 0.90; 95% CI 0.80, 1.02), or the other psychiatric conditions (OR range 0.95 to 1.06). Results were similar in sensitivity analyses. We found no evidence that genetically predicted serum urate has a causal effect on risk of MDD, anxiety, or other psychiatric disorders. Key Points • Clinicians are advised to be cautious about reducing the serum urate level too far in gout management, citing observational associations between low serum urate levels and various neuropsychiatric diseases. • In this two-sample Mendelian randomization study, we found no evidence for a causal link between genetically predicted serum urate level and the development of major depressive, anxiety, or other related psychiatric disorders. • Future revisions of clinical guidelines may need to reconsider recommendations regarding lower limits for serum urate levels.