Assessment Causality in Associations Between Serum Uric Acid and Risk of Schizophrenia: A Two-Sample Bidirectional Mendelian Randomization Study

Qianqian Luo,1–5,* Zheng Wen,1–5,* Yuanfan Li,1–5 Zefeng Chen,1–5 Xinyang Long,1–5 Yulan Bai,1–5 Shengzhu Huang,1–4 Yunkun Yan,1–4 Rui Lin,1–5 Zengnan Mo1–4,6 1Center for Genomic and Personalized Medicine, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 2Guangxi Key Laboratory for Genomic and Personalized Medicine, Nanning 530021, Guangxi, People’s Republic of China; 3Guangxi Collaborative Innovation Center for Genomic and Personalized Medicine, Nanning 530021, Guangxi, People’s Republic of China; 4Guangxi Key Laboratory of Colleges and Universities, Nanning 530021, Guangxi, People’s Republic of China; 5School of Public Health, Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China; 6Institute of Urology and Nephrology, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zengnan Mo; Rui LinCenter for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of ChinaTel/Fax +86771-5353342; +86771-5641040Email mozengnan@gxmu.edu.cn; linrui@gxmu.edu.cnPurpose: Although increasing lines of evidence showed associations between serum uric acid (UA) levels and schizophrenia, the causality and the direction of the associations remain uncertain. Thus, we aimed to assess whether the relationships between serum UA levels and schizophrenia are causal and to determine the direction of the association.Patients and Methods: Two-sample bidirectional Mendelian randomization (MR) analyses and various sensitivity analyses were performed utilizing the summary data from genome-wide association studies within the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium. Secondary MR analyses in both directions were conducted within summary data using genetic risk scores (GRSs) as instrumental variables.Results: Three MR methods provided no causal relationship between serum UA and schizophrenia. Furthermore, GRS approach showed similar results in the three MR methods after adjustment for heterogeneity. By contrast, inverse variance weighted method, weighted median and GRS approach suggested a causal effect of schizophrenia risk on serum UA after adjustment for heterogeneity (per 10-symmetric percentage increase in schizophrenia risk, beta: − 0.039, standard error (SE): 0.013, P = 0.003; beta: − 0.036, SE: 0.018, P = 0.043; beta: − 0.039, SE: 0.013, P = 0.002; respectively). Moreover, in both directions’ analyses, the heterogeneity and sensitivity tests suggested no strong evidence of bias due to pleiotropy.Conclusion: Schizophrenia may causally affect serum UA levels, whereas the causal role of serum UA concentrations in schizophrenia was not supported by our MR analyses. These findings suggest that UA may be a useful potential biomarker for monitoring treatment or diagnosis of schizophrenia rather than a therapeutic target for schizophrenia.Keywords: schizophrenia, uric acid, Mendelian randomization, genetic risk score, causality