The causal role of thyroid hormones in bipolar disorders: a two-sample Mendelian Randomization study

ABSTRACT Introduction Bipolar disorder is a complex psychiatric condition with distinctions between clinical subtypes including Type 1 and 2 disorders. Several studies have proposed thyroid hormones may be involved in the etiology of bipolar disorders. Methods 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, and Type 1 and 2 disorders, separately. Genome-wide association (GWAS) data from the Thyroidomics Consortium (up to 271,040 individuals of European ancestry) were used for thyroid function metrics. Bipolar disorder GWAS data included 41,917 cases and 371,549 controls (25,060 Type 1 and 6,781 Type 2 cases). We applied inverse variance weighted (IVW) methods for primary MR analysis, with MR Egger, weighted median, and weighted mode for sensitivity. Additional tests assessed horizontal pleiotropy and heterogeneity. Results Higher FT4 levels showed a protective causal effect against bipolar disorder (OR: 0.92, 95% CI: 0.86-0.97, p=4.58×10 −3 ) and a suggestive effect on Type 1 disorders (OR: 0.92, 95% CI: 0.86-0.99, p=3.21×10 −2 ). Elevated FT3 (OR: 1.18, 95% CI: 1.03-1.35, p=1.55×10 −2 ) and FT3/FT4 ratio (OR: 1.97, 95% CI: 1.02-3.82, p=4.46×10 −2 ) had suggestive harmful effects on Type 1 disorders. Sensitivity analyses showed consistent effects, with no significant horizontal pleiotropy or heterogeneity. Conclusions These findings highlight the protective role of FT4 and the potentially harmful effect of elevated FT3 in Type 1 bipolar disorder, highlighting the need for further research on thyroid hormone levels as a potential treatment strategy for Type 1 bipolar disorder.