Causal Association Between Antidepressant Use and Thyroid Disease Risk: A Two-Sample Mendelian Randomization Study

Abstract

Background: Observational studies have reported associations between antidepressant use and thyroid dysfunction; however, confounding precludes firm causal inference. This study aimed to evaluate the potential causal association between genetically predicted antidepressant use and the risks of Hashimoto’s thyroiditis, hypothyroidism and thyroid cancer using Mendelian randomisation (MR). Methods: Publicly available genome-wide association study (GWAS) summary statistics were used, with genetically predicted antidepressant use as the exposure and Hashimoto’s thyroiditis, hypothyroidism and thyroid cancer as the outcomes. Following data harmonisation, 13 single nucleotide polymorphisms (SNPs) meeting the prespecified significance threshold were selected as instrumental variables. The mean F statistic was 24.12 (range, 20.96–29.98), indicating that weak-instrument bias was unlikely. Inverse variance weighted (IVW) was used for the primary analysis, with MR-Egger regression, weighted-median and mode-based methods used in sensitivity analyses. Cochran ’s Q test was used to assess heterogeneity, and the MR-Egger intercept was used to assess directional horizontal pleiotropy. Results: Genetically predicted antidepressant use was positively associated with the risk of Hashimoto’s thyroiditis (IVW: odds ratio [OR] = 1.483, 95% confidence interval [CI]: 1.176–1.871; p = 0.001). A weak but statistically significant positive association was also observed for hypothyroidism (IVW: OR = 1.012, 95% CI: 1.002–1.023; p = 0.025). The directions of effect were generally consistent across sensitivity analyses. No evidence of an association with thyroid cancer was identified (IVW: p = 0.407). No evidence of bias was found in the heterogeneity test and the horizontal pleiotropy (p > 0.05), and the leave-one-out analysis confirmed the robustness of the results. Conclusions: This study provides genetic evidence of potential associations between antidepressant use and increased risks of Hashimoto’s thyroiditis and hypothyroidism. These findings support consideration of thyroid-function monitoring in patients receiving antidepressant treatment, particularly those with pre-existing thyroid risk factors.