On chromosome 14, TSHR (thyroid stimulating hormone receptor) spans the region around our most significant SNP (rs1035144, p = 4.7 × 10−7), and includes a cluster of SNPs with association p < 10−5 in intron 1. TSHR encodes a G protein-coupled transmembrane receptor for thyrothropin (thyroid stimulating hormone) and thyrostimulin, manifests some constitutive activity (i.e., ligand independent), and is a major controller of thyroid cell metabolism36,37,38. While the main tissue of interest and expression for TSHR is the thyroid gland, TSHR is expressed in other tissues including brain especially in neuron-rich areas (e.g., hippocampus)39.
TSHR codes for the major autoantigen in the autoimmune hyperthyroidism of Graves’ disease, which is associated (p < 10−20 with OR’s 1.4~1.5) with intron 1 polymorphisms40,41,42,43,44,45,46,47,48.
A recent population-based study found that 5,351 same-sex married men among the assayed population of 2,252,751 Danish men had an elevated rate ratio of Graves’ disease (RR = 1.88; 95% CI = 1.08–3.01), a finding which held when excluding men with HIV/AIDS49. The authors49 speculate on the possibility that a genetic (or other prenatal) factor might tie together this increased risk for a type of hyperthyroidism (Graves’ disease) with separate observations of lower body weight for homosexual versus heterosexual men (independent of diet or exercise)50,51,52.
Females with Graves’ disease have been reported to manifest biased X chromosome inactivation53,54,55,
and skewed X chromosome inactivation has also been reported in mothers of homosexual men compared to age-matched mothers of heterosexual men56. Furthermore, a recent retrospective chart review of 790 adolescents (8 to 17 years) previously admitted to a child psychiatry service found 15 mothers with a history of thyroid dysfunction during pregnancy, 16 adolescents with a history of same-sex attraction and/or gender nonconformity, and 12 overlapping mother-offspring pairs with both (p < 0.0001), suggestive of a possible relationship57. Thus converging findings, including suggestive evidence from the current study, point to a possible connection between thyroid function and sexual orientation in men.