Thyroid Function and Metabolic Syndrome: A Two-Sample Bidirectional Mendelian Randomization Study

Context: Thyroid function has been associated with metabolic syndrome (MetS) in a number of observational studies but the direction of effects and the exact causal mechanism of this relationship is still unknown.

Objective: To examine genetically predicted effects of thyroid function on MetS risk and its components, and vice versa, using large-scale summary genetic association data.

Methods: We performed a two-sample bidirectional Mendelian randomization (MR) study using summary statistics from the most comprehensive genome-wide association studies (GWAS) of thyroid-stimulating hormone (TSH, n = 119 715), free thyroxine (fT4, n = 49 269), MetS (n = 291 107), and components of MetS: waist circumference (n = 462 166), fasting blood glucose (n = 281 416), hypertension (n = 463 010), triglycerides (TG, n = 441 016) and high-density lipoprotein cholesterol (HDL-C, n = 403 943). We chose the multiplicative random effects inverse variance weighted (IVW) method as the main analysis. Sensitivity analysis included weighted median and mode analysis, as well as MR-Egger and Causal Analysis Using Summary Effect estimates (CAUSE).

Results: Our results suggest that higher fT4 levels lower the risk of developing MetS (OR = 0.96, P = .037). Genetically predicted fT4 was also positively associated with HDL-C (β = 0.02, P = .008), while genetically predicted TSH was positively associated with TG (β = 0.01, P = .044). These effects were consistent across different MR analyses and confirmed with the CAUSE analysis. In the reverse direction MR analysis, genetically predicted HDL-C was negatively associated with TSH (β = -0.03, P = .046) in the main IVW analysis.

Conclusion: Our study suggests that variations in normal-range thyroid function are causally associated with the diagnosis of MetS and with lipid profile, while in the reverse direction, HDL-C has a plausible causal effect on reference-range TSH levels.