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Is thyroid function associated with polycystic ovary syndrome? A bidirectional Mendelian randomization study

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Abstract

Objective

Some observational studies have suggested the association between thyroid function and polycystic ovary syndrome (PCOS). However, it remains to be determined whether these associations are causal or not. The aim of this study was to investigate the underlying causal association between different thyroid function status and PCOS.

Methods

Bidirectional Mendelian randomization (MR) analysis was conducted to explore the impact of different thyroid function statuses on PCOS. The study included 10,074 individuals with PCOS and 103,164 controls for the primary analysis, with validation analysis repeated in the FinnGen R9 and EstBB PCOS cohorts. Female-specific thyroid function GWAS data were obtained from European population, including Hyperthyroidism (22,383 cases and 54,288 controls) and Hypothyroidism (27,383 cases and 54,288 controls) from the UK Biobank, and TSH (54,288 cases and 72,167 controls) and FT4 (49,269 cases and 72,167 controls) within the reference range from the ThyroidOmics Consortium. Inverse variance weighting (IVW) was chosen as the principal method, and sensitivity analysis was conducted to test for the presence of horizontal pleiotropy or heterogeneity.

Results

The IVW analysis indicated nominal significance between normal TSH levels and PCOS after adjusted for age and BMI [OR (95% CI) = 0.78(0.62,0.97), P = 0.029], suggesting that maintaining normal TSH levels might act as a protective factor against the pathogenesis of PCOS. Besides, in order to increase the statistical power, we pooled PCOS GWAS above together by meta-analysis and found PCOS contributed to the occurrence of hyperthyroidism [OR(95%CI) = 1.37(0.73,2.57), P = 0.012]. However, no causal relationship was found after Bonferroni correction (P-value < 0.0031).

Conclusion

Although the MR analysis didn’t indicate genetic causal association between thyroid function and PCOS after Bonferroni correction. Further efforts are needed to interpret the potential causal relationship between thyroid function and PCOS in different age and BMI subgroup.

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Data availability

Publicly available data were analyzed in this study, which can be found in: UK Biobank (https://www.nealelab.is/ukbiobank), ThyroidOmicsConsortium (http://www.thyroidomics.com), FinnGenR9 (https://www.finngen.fi/en/access_results) and GWAS Catalog (https://www.ebi.ac.uk/). The original contributions presented in the study are included in the Article/Suppletmentary Material, further inquiries can be directed to the corresponding author.

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Acknowledgements

We express our gratitude to the patients and investigators who contributed to the GWAS. We thank the Figdraw platform for providing drawing materials. Q.Z. and B.Z. thank Dr. Liang Zheng from Department of Epidemiology and Public Health, Tongji University School of Medicine, Shanghai for statistical support of this paper.

Funding

This work was supported by the Natural Science Foundation of Shanghai (Grant Number:22ZR1448700) and Foundation of Shanghai Fifth People’s Hospital (Grant Number:2022WYZD01). The funders have no influence on the data collection, analyses or conclusions of the study.

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Author notes

  1. These authors contributed equally: Qinnan Zhang, Wencai Ke, Jun Ye

Authors and Affiliations

  1. Department of Endocrinology, Fifth People’s Hospital of Shanghai Fudan University, Shanghai, China

    Qinnan Zhang, Panpan Zhang, Qian Yang, Fanfan Pan, Kai Wang & Bingbing Zha

  2. Department of Clinical Laboratory Medicine, Fifth People’s Hospital of Shanghai Fudan University, Shanghai, China

    Wencai Ke

  3. Department of Obstetrics and Gynecology, Fifth People’s Hospital of Shanghai Fudan University, Shanghai, China

    Jun Ye

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Contributions

All authors contributed to the study conception and design. Q.Z. and B.Z. had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Q.Z., K.W. and B.Z. conceived and designed the study. Q.Z. and W.K. undertook the statistical analyses. Q.Z. and J.Y. wrote the first draft of the manuscript. K.W. and B.Z. are the study guarantor. Q.Z., P.Z., Q.Y. and F.P. interpreted data, reviewed the paper, and made critical revision of the manuscript for important intellectual content. All authors read and approved the final version of the manuscript.

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Correspondence to Kai Wang or Bingbing Zha.

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Zhang, Q., Ke, W., Ye, J. et al. Is thyroid function associated with polycystic ovary syndrome? A bidirectional Mendelian randomization study. Endocrine (2024). https://doi.org/10.1007/s12020-024-03756-w

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