Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Genomics and personalized strategies in nutrition

Serum uric acid is not associated with major depressive disorder in European and South American populations: a meta-analysis and two-sample bidirectional Mendelian Randomization study

Abstract

Objective

Although previous epidemiological studies have demonstrated that serum uric acid (SUA) is associated with major depressive disorder (MDD), these analyses are prone to biases. Here, we applied the Mendelian Randomization approach to determine whether SUA is causally associated with MDD.

Methods

We conducted a meta-analysis to evaluate the relationship between SUA and MDD, then applied summary data from the Global Urate Genetics Consortium and the Psychiatric Genomics Consortium to estimate their causal effect using a two-sample bidirectional Mendelian Randomization (MR) analysis. Thereafter, the causal effect was further researched using genetic risk scores (GRS) as instrumental variables (IVs).

Results

Results of a meta-analysis of articles comprising 6975 and 13,589 MDD patients and controls, respectively, revealed that SUA was associated with MDD (SMD = −0.690, 95% CI: −0.930 to −0.440, I2 = 97.4%, P < 0.001). In addition, the five MR methods revealed no causal relationship existed between SUA and MDD, which corroborated the results obtained via the GRS approach.

Conclusion

This paper found little evidence that this association between SUA and MDD is casual. Genetically, there was no significant causal association between SUA and MDD.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1
Fig. 2: Two-sample bidirectional Mendelian randomization analysis of the association between SUA and MDD.

Data availability

All datasets used in this study are publicly available, included in the main manuscript or its supplementary information files.

Code availability

The codes used for all analyses are available on request.

References

  1. Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, et al. Major depressive disorder. Nat Rev Dis Prim. 2016;2:16065.

    PubMed  Article  Google Scholar 

  2. Daniel HG, Jonathan F. Genetics and genomics of psychiatric disease. Science. 2015;349:1489–1494.

    Article  CAS  Google Scholar 

  3. Ronald CK, Evelyn JB. The epidemiology of depression across cultures. Annu Rev Public Health. 2013;34:119–138.

    Article  Google Scholar 

  4. Ron de G, Margreet ten H, Marlous T, Saskia van D. First-incidence of DSM-IV mood, anxiety and substance use disorders and its determinants: results from the Netherlands Mental Health Survey and Incidence Study-2. J Affect Disord. 2013;149:100–107.

    Article  Google Scholar 

  5. Evelyn B, Laura HA, Irving H, Nancy AS, Jordi A, Giovanni de G, et al. Cross-national epidemiology of DSM-IV major depressive episode. BMC Med. 2011;9:90.

    Article  Google Scholar 

  6. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet (London, England) 2015;386:743-800.

  7. Gilles P, Antonio S, Patrik V. Brain mechanisms for emotional influences on perception and attention: what is magic and what is not. Biol Psychol. 2013;92:492–512.

    Article  Google Scholar 

  8. Edward C, Guy MG, Seena F. Risks of all-cause and suicide mortality in mental disorders: a meta-review. World Psychiatry. 2014;13:153–160.

    Article  Google Scholar 

  9. Camougrand N, Rigoulet M. Aging and oxidative stress: studies of some genes involved both in aging and in response to oxidative stress. Respiration Physiol. 2001;128:393–401.

    CAS  Article  Google Scholar 

  10. de Melo LGP, Nunes SOV, Anderson G, Vargas HO, Barbosa DS, Galecki. P, et al. Shared metabolic and immune-inflammatory, oxidative and nitrosative stress pathways in the metabolic syndrome and mood disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2017;78:34–50.

    PubMed  Article  CAS  Google Scholar 

  11. Sarandol A, Sarandol E, Eker SS, Erdinc S, Vatansever E, Kirli S. Major depressive disorder is accompanied with oxidative stress: short-term antidepressant treatment does not alter oxidative–antioxidative systems. Hum Psychopharmacol: Clin Exp. 2007;22:67–73.

    CAS  Article  Google Scholar 

  12. Tao R, Li H. High serum uric acid level in adolescent depressive patients. J Affect Disord. 2015;174:464–466.

    CAS  PubMed  Article  Google Scholar 

  13. Bartoli F, Burnstock G, Crocamo C, Carra G. Purinergic Signaling and Related Biomarkers in Depression. Brain Sci. 2020;10.

  14. Mazzali M, Hughes J, Kim YG, Jefferson JA, Kang DH, Gordon KL, et al. Elevated uric acid increases blood pressure in the rat by a novel crystal-independent mechanism. Hypertension. 2001;38:1101–1106.

    CAS  PubMed  Article  Google Scholar 

  15. Capuron L, Su S, Miller AH, Bremner JD, Goldberg J, Vogt GJ, et al. Depressive symptoms and metabolic syndrome: is inflammation the underlying link? Biol Psychiatry. 2008;64:896–900.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Wium-Andersen MK, Ørsted DD, Nordestgaard BG. Elevated C-reactive protein and late-onset bipolar disorder in 78 809 individuals from the general population. Br J Psychiatry. 2016;208:138–145.

    PubMed  Article  Google Scholar 

  17. Lucca G, Comim CM, Valvassori SS, Réus GZ, Vuolo F, Petronilho F, et al. Increased oxidative stress in submitochondrial particles into the brain of rats submitted to the chronic mild stress paradigm. J Psychiatr Res. 2009;43:864–869.

    PubMed  Article  Google Scholar 

  18. Ames BN, Cathcart R, Schwiers E, Hochstein P. Uric acid provides an antioxidant defense in humans against oxidant- and radical-caused aging and cancer: a hypothesis. Proc Natl Acad Sci USA. 1981;78:6858–6862.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Gene LB, Jackilen S, Balz F, Jeffrey AK, Joseph FQ. Uric acid as a CNS antioxidant. J Alzheimer’s Dis. 2010;19:1331–1336.

    Article  CAS  Google Scholar 

  20. Bartoli F, Trotta G, Crocamo C, Malerba MR, Clerici M, Carra G. Antioxidant uric acid in treated and untreated subjects with major depressive disorder: a meta-analysis and meta-regression. Eur Arch Psychiatry Clin Neurosci. 2018;268:119–127.

    PubMed  Article  Google Scholar 

  21. Catherine NB, Mariska B, Peter GS, Harold S, Brenda WJHP. Uric acid in major depressive and anxiety disorders. J Affect Disord. 2018;225:684–690.

    Article  CAS  Google Scholar 

  22. Wium-Andersen MK, Kobylecki CJ, Afzal S, Nordestgaard BG. Association between the antioxidant uric acid and depression and antidepressant medication use in 96 989 individuals. Acta Psychiatr Scandinavica. 2017;136:424–433.

    CAS  Article  Google Scholar 

  23. Hemani G, Zheng J, Elsworth B, Wade KH, Haberland V, Baird D, et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife. 2018;7.

  24. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25:603–605.

    PubMed  Article  Google Scholar 

  25. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21:1539–1558.

    PubMed  Article  Google Scholar 

  26. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560.

    PubMed  PubMed Central  Article  Google Scholar 

  27. Kottgen A, Albrecht E, Teumer A, Vitart V, Krumsiek J, Hundertmark C, et al. Genome-wide association analyses identify 18 new loci associated with serum urate concentrations. Nat Genet. 2013;45:145–154.

    PubMed  Article  CAS  Google Scholar 

  28. Efstathiadou A, Gill D, McGrane F, Quinn T, Dawson J. Genetically Determined Uric Acid and the Risk of Cardiovascular and Neurovascular Diseases: A Mendelian Randomization Study of Outcomes Investigated in Randomized Trials. J Am Heart Assoc. 2019;8:e012738.

    PubMed  PubMed Central  Article  Google Scholar 

  29. Luo Q, Wen Z, Li Y, Chen Z, Long X, Bai Y, Huang S, et al. Assessment Causality in Associations Between Serum Uric Acid and Risk of Schizophrenia: A Two-Sample Bidirectional Mendelian Randomization Study. Clin Epidemiol. 2020;12:223–233.

    PubMed  PubMed Central  Article  Google Scholar 

  30. Keenan T, Zhao W, Rasheed A, Ho WK, Malik R, Felix JF, Young R, et al. Causal Assessment of Serum Urate Levels in Cardiometabolic Diseases Through a Mendelian Randomization Study. J Am Coll Cardiol. 2016;67:407–416.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Tang B, Yuan S, Xiong Y, He Q, Larsson SC. Major depressive disorder and cardiometabolic diseases: a bidirectional Mendelian randomisation study. Diabetologia. 2020.

  32. Howard DM, Adams MJ, Clarke TK, Hafferty JD, Gibson J, Shirali M, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci. 2019;22:343–352.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40:740–752.

    PubMed  Article  Google Scholar 

  34. Bowden J, Davey Smith G, Burgess S. Mendelian randomization with invalid instruments: effect estimation and bias detection through Egger regression. Int J Epidemiol. 2015;44:512–525.

    PubMed  PubMed Central  Article  Google Scholar 

  35. Bowden J, Davey, Smith G, Haycock PC, Burgess S. Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol. 2016;40:304–314.

    PubMed  PubMed Central  Article  Google Scholar 

  36. Hartwig FP, Davey Smith G, Bowden J. Robust inference in summary data Mendelian randomization via the zero modal pleiotropy assumption. Int J Epidemiol. 2017;46:1985–1998.

    PubMed  PubMed Central  Article  Google Scholar 

  37. Lewis CM, Vassos E. Prospects for using risk scores in polygenic medicine. Genome Med. 2017;9:96.

    PubMed  PubMed Central  Article  Google Scholar 

  38. Walter S, Mejía-Guevara I, Estrada K, Liu SY, Glymour MM. Association of a Genetic Risk Score With Body Mass Index Across Different Birth Cohorts. Jama. 2016;316:63–69.

    CAS  PubMed  Article  Google Scholar 

  39. Meng X, Huang X, Deng W, Li J, Li T. Serum uric acid a depression biomarker. PLoS One. 2020;15:e0229626.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Sohn H, Kwon M-S, Lee S-W, Oh J, Kim M-K, Lee S-H, et al. Effects of Uric Acid on the Alterations of White Matter Connectivity in Patients with Major Depression. Psychiatry Investig. 2018;15:593–601.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. Oliveira SR, Kallaur AP, Lopes J, Colado Simao AN, Vissoci Reiche EM, Delicato de Almeida ER, et al. Insulin resistance, atherogenicity, and iron metabolism in multiple sclerosis with and without depression: Associations with inflammatory and oxidative stress biomarkers and uric acid. Psychiatry Res. 2017;250:113–120.

    CAS  PubMed  Article  Google Scholar 

  42. Peng Y-F, Xiang Y, Wei Y-S. The significance of routine biochemical markers in patients with major depressive disorder. Sci Rep. 2016;6.

  43. Wiener C, Rassier GT, Kaster MP, Jansen K, Pinheiro RT, Klamt F, et al. Gender-based differences in oxidative stress parameters do not underlie the differences in mood disorders susceptibility between sexes. Eur Psychiatry. 2014;29:58–63.

    CAS  PubMed  Article  Google Scholar 

  44. Wen S, Cheng M, Wang H, Yue J, Wang H, Li G, et al. Serum uric acid levels and the clinical characteristics of depression. Clin Biochem. 2012;45:49–53.

    CAS  PubMed  Article  Google Scholar 

  45. Yanik M, Erel O, Kati M. The relationship between potency of oxidative stress and severity of depression. Acta Neuropsychiatrica. 2004;16:200–203.

    PubMed  Article  Google Scholar 

  46. Kotan VO, Sarandol E, Kirhan E, Ozkaya G, Kirli S. Effects of long-term antidepressant treatment on oxidative status in major depressive disorder: a 24-week follow-up study. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:1284–1290.

    CAS  PubMed  Article  Google Scholar 

  47. Chaudhari K, Khanzode S, Khanzode S, Dakhale G, Saoji A, Sarode S. Clinical correlation of alteration of endogenous antioxidant-uric acid level in major depressive disorder.pdf. 2010.

  48. Mondin TC, Cardoso TDA, Moreira FP, Wiener C, Oses JP, de Mattos Souza LD, et al. Circadian preferences, oxidative stress and inflammatory cytokines in bipolar disorder: A community study. J Neuroimmunol. 2016;301:23–29.

    CAS  PubMed  Article  Google Scholar 

  49. Wang L, Song R, Chen Z, Wang J, Ling F. Prevalence of depressive symptoms and factors associated with it in type 2 diabetic patients: a cross-sectional study in China. BMC Public Health 2015;15.

  50. Bartoli F, Crocamo C, Gennaro GM, Castagna G, Trotta G, Clerici M, et al. Exploring the association between bipolar disorder and uric acid: A mediation analysis. J Psychosom Res. 2016;84:56–59.

    PubMed  Article  Google Scholar 

  51. Li Y, Zhao L, Yu D, Ding G. Associations between serum uric acid and depression among middle-aged and elderly participants in China. Psychol Health Med. 2019;24:1277–1286.

    PubMed  Article  Google Scholar 

  52. Kobrosly R, van Wijngaarden E. Associations between immunologic, inflammatory, and oxidative stress markers with severity of depressive symptoms: an analysis of the 2005-2006 National Health and Nutrition Examination Survey. Neurotoxicology. 2010;31:126–133.

    CAS  PubMed  Article  Google Scholar 

  53. Black CN, Bot M, Scheffer PG, Snieder H, Penninx BWJH. Uric acid in major depressive and anxiety disorders. J Affect Disord. 2018;225:684–690.

    CAS  PubMed  Article  Google Scholar 

  54. Li G, Miao J, Sun W, Song X, Lan Y, Zhao X, et al. Lower Serum Uric Acid Is Associated With Post-Stroke Depression at Discharge. Front Psychiatr. 2020;11.

  55. Gu Y, Han B, Wang L, Chang Y, Zhu L, Ren W, et al. Low Serum Levels of Uric Acid are Associated With Development of Poststroke Depression. Medicine. 2015;94:e1897.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. Kesebir S, Yaylaci ET, Suner O, Gultekin BK. Uric acid levels may be a biological marker for the differentiation of unipolar and bipolar disorder: The role of affective temperament. J Affect Disord. 2014;165:131–134.

    CAS  PubMed  Article  Google Scholar 

  57. Wigner P, Czarny P, Galecki P, Su K-P, Sliwinski T. The molecular aspects of oxidative & nitrosative stress and the tryptophan catabolites pathway (TRYCATs) as potential causes of depression. Psychiatry Res. 2018;262:566–574.

    CAS  PubMed  Article  Google Scholar 

  58. Gałecki P, Szemraj J, Bieńkiewicz M, Zboralski K, Gałecka E. Oxidative stress parameters after combined fluoxetine and acetylsalicylic acid therapy in depressive patients. Hum Psychopharmacol. 2009;24:277–286.

    PubMed  Article  CAS  Google Scholar 

  59. Morris G, Berk M, Klein H, Walder K, Galecki P, Maes M. Nitrosative Stress, Hypernitrosylation, and Autoimmune Responses to Nitrosylated Proteins: New Pathways in Neuroprogressive Disorders Including Depression and Chronic Fatigue Syndrome. Mol Neurobiol. 2017;54:4271–4291.

    CAS  PubMed  Article  Google Scholar 

  60. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30:470–476.

    CAS  PubMed  Google Scholar 

  61. Kodydková J, Vávrová L, Zeman M, Jirák R, Macásek J, Stanková B, et al. Antioxidative enzymes and increased oxidative stress in depressive women. Clin Biochem. 2009;42:1368–1374.

    PubMed  Article  CAS  Google Scholar 

  62. Gautam M, Agrawal M, Gautam M, Sharma P, Gautam A, Gautam S. Role of antioxidants in generalised anxiety disorder and depression. Indian J Psychiatry. 2012;54:244–247.

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge the Global Urate Genetics Consortium (GUGC) and the Psychiatric Genomics Consortium (PGC) for supplying the summary data. This study was funded by the Major Project of Guangxi Innovation Driven (AA18118016), National Key Research and Development Program of China (2017YFC0908000), Scientific Research and Technology Development Program of Guangxi (15277004).

Author information

Authors and Affiliations

Authors

Contributions

ZC and SL designed research; YB and JL conducted research; JL and ZM analyzed data, and ML, SX and SSH wrote the paper. ZC had primary responsibility for the final content. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zefeng Chen or Jianxiong Long.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Chen, Z., Liang, S., Bai, Y. et al. Serum uric acid is not associated with major depressive disorder in European and South American populations: a meta-analysis and two-sample bidirectional Mendelian Randomization study. Eur J Clin Nutr (2022). https://doi.org/10.1038/s41430-022-01165-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41430-022-01165-8

Search

Quick links