Abstract

Gender Dysphoria (GD) is commonly thought to arise from discrepant cerebral and gonadal sexual differentiation. Since testosterone and estradiol are known to be involved in brain masculinization, we hypothesized the interaction between the estrogen receptors ERα and ERβ, AR, CYP19A1, and CYP17A1 in GD. The aim of the investigation was the molecular analysis of seven polymorphisms [(TA)n-ERα (rs3138774), PvuII-ERα (rs2234693), XbaI-ERα (rs9340799), (CA)n-ERβ, (CAG)n-AR, (TTTA)n-CYP19A1, and MspA1-CYP17A1 (rs743572)] in a population of 426 FtM, 588 MtF, 599 control XX women and 728 control XY men. Genotype and haplotype frequencies were analyzed by SPSS® 23.0, with a p value below 0.05 being significant. The mean number of tandem repeats was analyzed by the Mann–Whitney U-test. The allele and genotype frequencies were analyzed by chi-squared test. The association and linkage disequilibrium analyses were performed using the free online software SNPStats. Following Blanchard typology, the MtF group consisted of homosexual (erotic attraction to individuals with the same biological sex), non homosexual (erotic attraction to subjects with the other biological sex), or bisexual individuals, early or non-early onset. The analysis of the means was carried out with respect to biological sex (FtM vs. control XX and MtF vs. control XY), sexual orientation (homosexual, non homosexual and bisexual) and time of onset (early vs. non-early). The analysis showed significant differences for the (CA)n-ERβ polymorphism in the FtM group vs. the XX control population. Statistical differences were also found for allele and genotype frequencies for polymorphisms XbaI-ERα and ERβ in the FtM vs. control XX groups. Interaction analysis between polymorphisms showed an association between ERα and β and GD in both biological sexes, but with some differences. In biological females we found a direct association between the number of CA repeats in ERβ and GD such that the greater the number of CA repeats, the greater the probability of GD in the FtM population. We also found that ERα is involved in the genetic basis of GD in the FtM group. The XbaI-ERα allele, genotype and also haplotype frequencies differed significantly between the FtM and XX control groups. The single nucleotide change A→G in the first intron of the ESR1 gene seems to have a significant effect on the genetic basis of GD: the genotype A/A implied a great susceptibility to GD in the FtM group, while the genotype A/G conferred a protective effect. In biological males the cross interaction between the polymorphisms ERβ, CYP19A1 and XbaI-ERα showed statistical significance only when adjusted by the AR polymorphism. In the case of XY individuals, carrying a short (S) allele from the ERβ polymorphism together with a long (L) allele for CYP19A1, a G allele for XbaI-ERα and an S allele for AR, imply a very high risk of GD.