Abstract
This study explores the causal link between celiac disease (CeD) and osteoporosis and measures the intermediary role of thyroid dysfunction in this relationship. Using genome-wide association studies summary data, we performed two-sample Mendelian randomization (MR) studies on genetically predicted CeD (11,812 cases, 23,649 individuals) and osteoporosis (462,933 samples, 7547 cases). We applied two-step MR to quantify the influence of CeD on osteoporosis, two-sample MR to validate the effects of potential mediators (type 1 and 2 diabetes, hyperthyroidism, hypothyroidism), and multivariate MR to estimate the effects of hyperthyroidism and hypothyroidism, and their joint influence. CeD contributes to the risk of osteoporosis (OR: 1.001, 95% CI: 1.000-1.001, P = 4.36E-07) and promotes both hyperthyroidism (OR: 1.001, 95% CI: 1.000-1.002, P = .0003) and hypothyroidism (OR: 1.004, 95% CI: 1.002-1.005, P = 2.24E-06). Hyperthyroidism and hypothyroidism account for 3.17% (95% CI: 2.29%, 5.19%) and 2.24% (95% CI: 1.61%, 3.65%) of the total effect of CeD on osteoporosis, respectively. Together, they explain 34.31% (95% CI: 24.72%, 56.05%) of the total effect. Our study confirms the causal effect between CeD and osteoporosis risk, in which thyroid dysfunction plays a mediating role. Increasing population-level thyroid function screening may lower this risk.