Skip to main content
SpringerLink
Log in

No causal relationship between thyroid function and Parkinson’s disease: A bidirectional Mendelian randomization study

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Background

Parkinson's disease (PD) is the second most prevalent degenerative disease globally. While observational studies have demonstrated a correlation between thyroid function and PD, the causal relationship between these two factors remains uncertain.

Methods

A bidirectional Mendelian randomization (MR) analysis was performed to explore the causal relationship between thyroid function (free thyroxine [FT4], thyroid-stimulating hormone [TSH], hyperthyroidism, and hypothyroidism) and PD. GWAS summary-level statistics of thyroid function and PD were obtained from publicly available GWAS databases. The inverse variance weighted method was the main MR approach to assess causal associations. In addition, two additional MR methods (MR-Egger regression and weighted median) were performed to supplement the IVW. Furthermore, various sensitivity tests were performed to verify the reliability of the MR findings: (i) Heterogeneity was examined by Cochrane's Q test. (ii) Horizontal pleiotropy was assessed by the MR-Egger intercept test and MR-PRESSO global test. (iii) The robustness of MR results was estimated using the leave-one-out method.

Results

Various MR results showed that FT4, TSH, hyperthyroidism, and hypothyroidism did not causally affect PD (P > 0.05). Likewise, PD did not causally affect FT4, TSH, hyperthyroidism, and hypothyroidism (P > 0.05). Cochrane's Q test indicated that MR analysis was not affected by significant heterogeneity (P > 0.05). MR-Egger intercept test and MR-PRESSO global test indicated that MR analysis was not affected by a remarkable horizontal pleiotropy (P > 0.05). The leave-one-out method demonstrated the stability of MR results.

Conclusion

MR analysis did not support a causal relationship between thyroid function and PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

The original contributions presented in this study are included in the article/Supplementary material.

References

  1. Poewe W, Seppi K, Tanner CM, Halliday GM, Brundin P, Volkmann J, Schrag AE, Lang AE (2017) Parkinson disease. Nat Rev Dis Primers 3:17013. https://doi.org/10.1038/nrdp.2017.13

    Article  PubMed  Google Scholar 

  2. Armstrong MJ, Okun MS (2020) Diagnosis and Treatment of Parkinson Disease: A Review. JAMA 323:548–560. https://doi.org/10.1001/jama.2019.22360

    Article  PubMed  Google Scholar 

  3. Ascherio A, Schwarzschild MA (2016) The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 15:1257–1272. https://doi.org/10.1016/s1474-4422(16)30230-7

    Article  PubMed  Google Scholar 

  4. Vázquez-Vélez GE, Zoghbi HY (2021) Parkinson’s Disease Genetics and Pathophysiology. Annu Rev Neurosci 44:87–108. https://doi.org/10.1146/annurev-neuro-100720-034518

    Article  CAS  PubMed  Google Scholar 

  5. Stepien BK, Huttner WB (2019) Transport, Metabolism, and Function of Thyroid Hormones in the Developing Mammalian Brain. Front Endocrinol (Lausanne) 10:209. https://doi.org/10.3389/fendo.2019.00209

    Article  PubMed  Google Scholar 

  6. Schroeder AC, Privalsky ML (2014) Thyroid hormones, t3 and t4, in the brain. Front Endocrinol (Lausanne) 5:40. https://doi.org/10.3389/fendo.2014.00040

    Article  PubMed  Google Scholar 

  7. Charoenngam N, Rittiphairoj T, Ponvilawan B, Prasongdee K (2022) Thyroid Dysfunction and Risk of Parkinson’s Disease: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 13:863281. https://doi.org/10.3389/fendo.2022.863281

    Article  PubMed  Google Scholar 

  8. Lee EH, Kim SM, Kim CH, Pagire SH, Pagire HS, Chung HY, Ahn JH, Park CH (2019) Dopamine neuron induction and the neuroprotective effects of thyroid hormone derivatives. Sci Rep 9:13659. https://doi.org/10.1038/s41598-019-49876-6

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. Villanueva I, Alva-Sánchez C, Pacheco-Rosado J (2013) The role of thyroid hormones as inductors of oxidative stress and neurodegeneration. Oxid Med Cell Longev 2013:218145. https://doi.org/10.1155/2013/218145

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Henchcliffe C, Beal MF (2008) Mitochondrial biology and oxidative stress in Parkinson disease pathogenesis. Nat Clin Pract Neurol 4:600–609. https://doi.org/10.1038/ncpneuro0924

    Article  CAS  PubMed  Google Scholar 

  11. Chen SF, Yang YC, Hsu CY, Shen YC (2020) Risk of Parkinson’s disease in patients with hypothyroidism: A nationwide population-based cohort study. Parkinsonism Relat Disord 74:28–32. https://doi.org/10.1016/j.parkreldis.2020.04.001

    Article  PubMed  Google Scholar 

  12. Lin SR, Chen SF, Yang YC, Hsu CY, Shen YC (2021) Association between hyperthyroidism and risk of incident in Parkinson’s disease. Endocr Connect 10:13–20. https://doi.org/10.1530/ec-20-0554

    Article  PubMed  Google Scholar 

  13. Paternoster L, Tilling K, Davey Smith G (2017) Genetic epidemiology and Mendelian randomization for informing disease therapeutics: Conceptual and methodological challenges. PLoS Genet 13:e1006944. https://doi.org/10.1371/journal.pgen.1006944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hu X, Zhao J, Lin Z, Wang Y, Peng H, Zhao H, Wan X, Yang C (2022) Mendelian randomization for causal inference accounting for pleiotropy and sample structure using genome-wide summary statistics. Proc Natl Acad Sci U S A 119:e2106858119. https://doi.org/10.1073/pnas.2106858119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Teumer A, Chaker L, Groeneweg S, Li Y, Di Munno C, Barbieri C, Schultheiss UT, Traglia M, Ahluwalia TS, Akiyama M et al (2018) Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat Commun 9:4455. https://doi.org/10.1038/s41467-018-06356-1

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D, Tan M, Kia DA, Noyce AJ, Xue A et al (2019) Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol 18:1091–1102. https://doi.org/10.1016/s1474-4422(19)30320-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. VanderWeele TJ, TchetgenTchetgen EJ, Cornelis M, Kraft P (2014) Methodological challenges in mendelian randomization. Epidemiology 25:427–435. https://doi.org/10.1097/ede.0000000000000081

    Article  PubMed  PubMed Central  Google Scholar 

  18. Pierce BL, Ahsan H, Vanderweele TJ (2011) Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 40:740–752. https://doi.org/10.1093/ije/dyq151

    Article  PubMed  Google Scholar 

  19. Pagoni P, Dimou NL, Murphy N, Stergiakouli E (2019) Using Mendelian randomisation to assess causality in observational studies. Evid Based Ment Health 22:67–71. https://doi.org/10.1136/ebmental-2019-300085

    Article  PubMed  PubMed Central  Google Scholar 

  20. Bowden J, Davey Smith G, Haycock PC, Burgess S (2016) Consistent Estimation in Mendelian Randomization with Some Invalid Instruments Using a Weighted Median Estimator. Genet Epidemiol 40:304–314. https://doi.org/10.1002/gepi.21965

    Article  PubMed  PubMed Central  Google Scholar 

  21. Burgess S, Thompson SG (2017) Interpreting findings from Mendelian randomization using the MR-Egger method. Eur J Epidemiol 32:377–389. https://doi.org/10.1007/s10654-017-0255-x

    Article  PubMed  PubMed Central  Google Scholar 

  22. Hemani, G, Zheng, J, Elsworth, B, Wade, KH, Haberland, V, Baird, D, Laurin, C, Burgess, S, Bowden, J, Langdon, R et al. (2018) The MR-Base platform supports systematic causal inference across the human phenome. Elife 7. https://doi.org/10.7554/eLife.34408

  23. Verbanck M, Chen CY, Neale B, Do R (2018) Detection of widespread horizontal pleiotropy in causal relationships inferred from Mendelian randomization between complex traits and diseases. Nat Genet 50:693–698. https://doi.org/10.1038/s41588-018-0099-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kim JH, Lee HS, Ahn JH, Oh JK, Chang IB, Song JH, Wee JH, Min CY, Yoo DM, Choi HG (2021) Association Between Thyroid Diseases and Parkinson’s Disease: A Nested Case-Control Study Using a National Health Screening Cohort. J Parkinsons Dis 11:211–220. https://doi.org/10.3233/jpd-202265

    Article  PubMed  Google Scholar 

  25. Lee K, Lim CY (2019) Mendelian Randomization Analysis in Observational Epidemiology. J Lipid Atherosclerosis 8:67–77. https://doi.org/10.12997/jla.2019.8.2.67

    Article  CAS  Google Scholar 

  26. Xu J, Zhao C, Liu Y, Xu C, Qin B, Liang H (2022) Genetic correlation between thyroid hormones and Parkinson’s disease. Clin Exp Immunol 208:372–379. https://doi.org/10.1093/cei/uxac044

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the ThyroidOmics consortium, International Parkinson Disease Genomics Consortium, and IEU OpenGWAS project database for providing public access to GWAS summary statistics.

Funding

This research was funded by the National Natural Science Foundation of Hunan Province (2022JJ70069).

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China

    Youjie Zeng & Si Cao

  2. Department of Neurology, Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China

    Heng Yang

Authors
  1. Youjie Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Si Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Heng Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Youjie Zeng: Conceptualization, Methodology, Validation, Investigation, Data Curation, Writing—Original Draft, Writing—Review & Editing, Visualization; Si Cao: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Data Curation, Writing—Review & Editing; Heng Yang: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Supervision, Project administration, Funding acquisition.

Corresponding author

Correspondence to Heng Yang.

Ethics declarations

Ethical approval and Informed consent

The study utilized publicly available de-identified data from participant studies that had previously been approved by an ethics committee, thereby obviating the need for additional ethical approval and informed consent for this research.

Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (PDF 569 KB)

Supplementary file2 (XLSX 44 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zeng, Y., Cao, S. & Yang, H. No causal relationship between thyroid function and Parkinson’s disease: A bidirectional Mendelian randomization study. Neurol Sci 45, 1481–1487 (2024). https://doi.org/10.1007/s10072-023-07176-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-023-07176-y

Keywords

Search

Navigation