Background: Bipolar disorder is a complex psychiatric condition with notable differences among its clinical subtypes including Type 1 and 2 disorders. Several studies have proposed that thyroid hormones may be involved in the etiology of bipolar disorders. Aims: This study employed a two-sample Mendelian Randomization (MR) approach to investigate the causal relationships between six thyroid hormone metrics (TSH, FT4, FT3, TT3, FT3/FT4, and TT3/FT4) and bipolar disorder, as well as Type 1 and 2 disorders, separately. Methods: We used GWAS summary statistics from the Thyroidomics Consortium (involving up to 271,040 individuals of European ancestry) to identify instruments for thyroid function metrics in MR analyses. Additionally, we included GWAS data for bipolar disorder, involving 41,917 cases and 371,549 controls of European ancestry, with 25,060 Type 1 and 6,781 Type 2 bipolar disorder cases. Results: We found that higher FT4 levels may have a protective causal effect against bipolar disorder and a suggestive causal effect on Type 1 bipolar disorder. In contrast, elevated FT3 levels and an increased FT3/FT4 ratio showed a suggestive harmful causal effect on Type 1 bipolar disorder. These associations remained robust across various MR methods, minimizing the likelihood of pleiotropy affecting our results. Conclusion: Our findings align with previous research but uniquely highlight the potentially harmful impact of elevated FT3 on Type 1 bipolar disorder. This study strengthens the evidence for FT4's role in bipolar disorder and highlights the need for further research into targeting thyroid hormone levels as a potential treatment strategy for Type 1 bipolar disorder.

The authors have declared no competing interest.

This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health (award number T32GM007281) and the Susan G. Komen Breast Cancer Foundation (TREND21675016 and SAC210203).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

All GWAS summary statistics utilized in this study are previously published and publicly available and for academic use without restriction. GWAS summary statistics for thyroid function utilized in this study are downloadable from the Thyroidomics Consortium at https://transfer.sysepi.medizin.uni-greifswald.de/thyroidomics/datasets/. GWAS summary statistics for bipolar disorders utilized in this study are downloadable from the Psychiatric Genomics Consortium at https://pgc.unc.edu/for-researchers/download-results/.

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Code for all analyses performed in this study are available at https://github.com/james-li-projects/MR_Thyroid_BPD.