Causal Association Between Serum Thyrotropin and Obesity: A Bidirectional, Mendelian Randomization Study

Context: The association between serum thyrotropin (TSH) and obesity traits has been investigated previously in several epidemiological studies. However, the underlying causal association has not been established. Objective: This work aimed to determine and analyze the causal association between serum TSH level and obesity-related traits (body mass index [BMI] and obesity). Methods: The latest genome-wide association studies (GWASs) on TSH, BMI, and obesity were searched to obtain full statistics. Bidirectional 2-sample mendelian randomization (MR) was performed to explore the causal relationship between serum TSH and BMI and obesity. The inverse variance-weighted (IVW) and MR-Egger methods were used to combine the estimation for each single-nucleotide variation (formerly single-nucleotide polymorphism). Based on the preliminary MR results, free thyroxine (fT4) and free 3,5,3'-triiodothyronine (fT3) levels were also set as outcomes to further analyze the impact of BMI on them. BMI and obesity were treated as the outcomes to evaluate the effect of serum TSH on them, and TSH was set as the outcome to estimate the effect of BMI and obesity on it. Results: IVW and MR-Egger results both indicated that genetically driven serum TSH did not causally lead to changes in BMI or obesity. Moreover, the IVW method showed that the TSH level could be significantly elevated by genetically predicted high BMI (beta=.038, SE=0.013, P=.004). In further MR analysis, the IVW method indicated that BMI could causally increase the fT3 (beta=10.123, SE = 2.523, P < .001) while not significantly affecting the fT4 level. Conclusion: Together with fT3, TSH can be significantly elevated by an increase in genetically driven BMI.