Bidirectional Mendelian randomization and mediation analysis of million-scale data reveal causal relationships between thyroid-related phenotypes, smoking, and lung cancer

Emerging evidence highlights the role of thyroid hormones in cancer, although findings are controversial. Research on thyroid-related traits in lung carcinogenesis is limited. Using UK Biobank data, we performed bidirectional Mendelian randomization (MR) to assess causal associations between lung cancer risk and thyroid dysfunction (hypothyroidism and hyperthyroidism) or functional traits (free thyroxine FT4 and normal-range thyroid-stimulating hormone TSH). Furthermore, in the smoking-behavior-stratified MR analysis, we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking behaviors and lung cancer. We demonstrated significant associations between lung cancer risk and hypothyroidism (hazard ratio HR = 1.14, 95% confidence interval CI = 1.03–1.26, P = 0.009) and hyperthyroidism (HR = 1.55, 95% CI = 1.29–1.87, P = 1.90 × 10⁻⁶) in the UKB. Moreover, the MR analysis indicated a causal effect of thyroid dysfunction on lung cancer risk (OR_{inverse variance weighted IVW} = 1.09, 95% CI = 1.05–1.13, P = 3.12 × 10⁻⁶ for hypothyroidism; OR_IVW = 1.08, 95% CI = 1.04–1.12, P = 8.14 × 10⁻⁵ for hyperthyroidism). We found that FT4 levels were protective against lung cancer risk (OR_IVW = 0.93, 95% CI = 0.87–0.99, P = 0.030). Additionally, the stratified MR analysis demonstrated distinct causal effects of thyroid dysfunction on lung cancer risk among smokers. Hyperthyroidism mediated the effect of smoking behaviors, especially the age of smoking initiation (17.66% mediated), on lung cancer risk. Thus, thyroid dysfunction phenotypes play causal roles in lung cancer development exclusively among smokers and act as mediators in the causal pathway from smoking to lung cancer.