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, though findings are controversial. Research on thyroid-related traits in lung carcinogenesis is limited. Using UK Biobank data, we conducted bidirectional Mendelian randomization (MR) to assess causal links between lung cancer risk and thyroid dysfunction (hypothyroidism/hyperthyroidism) or function traits (free thyroxine [FT4], normal-range TSH). Furthermore, in the smoking-behavior stratified MR analysis, we evaluated the mediating effect of thyroid-related phenotypes on the association between smoking phenotype and lung cancer. We confirmed significant associations between lung cancer risk and hypothyroidism (hazards ratio [HR] = 1.14, 95% confidence interval [CI] = 1.03-1.26, P = 0.009) as well as 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 the distinct causal effect of thyroid dysfunction on lung cancer risk among smokers. Hyperthyroidism mediated the effect of smoking behavior, 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.