Causal Relationships between Obesity and Thyroid Function and Thyroid Disease: A Two-Sample Mendelian Randomization Study

Abstract OBJECTIVE: We conducted a Mendelian Randomization(MR) study to investigate the causal association between obesity and thyroid function and thyroid disease. RESEARCH DESIGN AND METHODS: Uncorrelated genetic variants associated with Body Mass Index(BMI) (n = 543), Waist-hip Ratio(WHR)(n = 357), WHR adjusted for BMI (WHRadjBMI) (n = 330) at the genome-wide significance were selected as exposure instrument variables(IV). Genetic associations for 13 serum markers of thyroid function and 21 thyroid diseases were obtained from THE THYROIDOMICS CONSORTIUM, IEU, and FinnGen as outcome IVs. Heterogeneity and pleiotropy of the identified IVs were confirmed using the Q-test, the leave-one-out sensitivity test, the MR-Egger intercept test, and the MR Pleiotropy RESidual Sum and outliers test (MR-PRESSO). Then, MR analysis was performed using five different models. RESULTS: The results of the MR analysis showed causal relationships between obesity and two serum markers of thyroid function and three thyroid diseases. Genetic prediction of higher BMI reduced serum FT4 level (OR = 0.934, 95%CI 0.902, 0.996; P = 0.0001) while increasing the risk of Autoimmune hypothyroidism (OR = 1.248, 95%CI 1.170, 1.331; P = 0. 00000000002) and Nontoxic multinodular goiter (OR = 1.236, 95%CI 1.090, 1.402; P < 0.001). Genetic prediction of elevated WHRadjBMI increased serum FT3 levels (OR = 1.093, 95%CI 1.049, 1.139; P = 0.00002) and the risk of Malignant tumors of the thyroid gland (OR = 1.490, 95%CI 1.170, 1.897; P = 0.0012). The sensitivity analyses demonstrated the robustness of these findings. No significant causal relationship was found between obesity and other serum markers of thyroid function or thyroid disease. CONCLUSIONS: Causal relationships between obesity and serum FT3 levels, serum FT4 levels, Autoimmune hypothyroidism, Nontoxic multinodular goiter, and Thyroid malignancies. This result explains the chicken-and-egg problem between obesity and the thyroid gland and emphasizes the role of obesity on the thyroid gland.