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

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Abstract

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.

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Fig. 1

Data availability

All summary GWAS data are publicly available from the respective authors; details are provided in supplementary materials.

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Funding

YM is supported by grants from National Natural Science Foundation of China (81973663 and 81873269), and the talent project of Zhejiang Association for Science and Technology (2018YCGC003).

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Author notes

  1. Sizheng Steven Zhao and Yu Qian contributed equally to this work.

Authors and Affiliations

  1. Musculoskeletal Biology, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK

    Sizheng Steven Zhao

  2. Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang Chinese Medical University, Zhejiang, 310053, Hangzhou, China

    Yu Qian, Chengping Wen & Yingying Mao

  3. Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK

    Sarah L Mackie

  4. National Institute for Health Research Leeds Biomedical Research Centre, Leeds Teaching Hospitals, University of Leeds, Leeds, UK

    Sarah L Mackie

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  1. Sizheng Steven Zhao
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  2. Yu Qian
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  4. Chengping Wen
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  5. Yingying Mao
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All authors contributed to the manuscript and approved its submission.

Corresponding author

Correspondence to Yingying Mao.

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Conflict of interest

SLM: Consultancy on behalf of institution to: Roche/Chugai, Sanofi. Investigator on industry-sponsored clinical trials for: GSK, Sanofi. Attendance at EULAR2019 supported by Roche. Co-applicant on research grants from Vifor and Roche. Patron of the charity PMRGCAuk. This publication presents independent research supported by the Leeds Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The other authors have disclosed no conflicts of interest.

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Zhao, S.S., Qian, Y., Mackie, S.L. et al. Genetically predicted serum urate levels have no causal role on depression or other psychiatric disorders. Clin Rheumatol 40, 3729–3733 (2021). https://doi.org/10.1007/s10067-021-05718-3

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  • DOI: https://doi.org/10.1007/s10067-021-05718-3

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