Genetic evidence for causality between thyroid function and endometriosis: A bidirectional 2-sample Mendelian randomization study

Abstract

Accumulating observational evidence suggests an association between thyroid function and endometriosis, though the causal relationship remains unclear. To investigate potential bidirectional causal relationships, including for endometriosis subtypes, we conducted a bidirectional 2-sample Mendelian randomization (MR) analysis utilizing summary genetic data. Data sources included the ThyroidOmics Consortium (free thyroxine [FT4], thyroid-stimulating hormone [TSH], subclinical hypothyroidism, subclinical hyperthyroidism: N = 72,167, thyroid peroxidase antibody [TPOAb]: N = 18,297), IEU database (N = 3,37,159), and FinnGen Consortium R9 (8288 cases and 68,969 controls). The inverse variance weighted method served as the primary analysis, supplemented by sensitivity analyses to evaluate pleiotropy and heterogeneity, alongside subgroup analyses. Forward MR analysis revealed that genetically predicted FT4 was negatively associated with total endometriosis (odds ratio [OR] = 0.886, 95% confidence interval [CI]: 0.794–0.989, P = .031). Furthermore, overt hypothyroidism (OR = 0.227, 95% CI: 0.056–0.916, P = .037) and subclinical hypothyroidism (OR = 0.859, 95% CI: 0.762–0.969, P = .013) were negatively associated with endometriosis with occurring infertility, whereas subclinical hyperthyroidism was negatively associated with the uterine subtype (OR = 0.919, 95% CI: 0.863–0.979, P = .008). Conversely, TSH levels within the normal range were positively associated with the uterine subtype (OR = 1.195, 95% CI: 1.031–1.386, P = .018). Reverse MR analysis did not reveal any causality between endometriosis and thyroid function. This study provides genetic evidence for unidirectional causal effects of thyroid function on specific endometriosis phenotypes in Europeans, with no reverse causality. These findings warrant replication in independent cohorts and well-designed prospective studies.