Context: There is a likely genetic component to gender dysphoria, but association study data have been equivocal.
Objective: We explored the specific hypothesis that gender dysphoria in transgender women is associated with variants in sex hormone-signaling genes responsible for undermasculinization and/or feminization.
Design: Subject-control analysis included 380 transgender women and 344 control male subjects. Associations and interactions were investigated between functional variants in 12 sex hormone-signaling genes and gender dysphoria in transgender women.
Setting: Patients were recruited from the Monash Gender Clinic, Monash Health, Melbourne, Australia, and the University of California, Los Angeles.
Patients: Caucasian (non-Latino) transgender women were recruited who received a diagnosis of transsexualism [Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV) or gender dysphoria (DSM-V)] pre- or postoperatively. Most were receiving hormone treatment at the time of recruitment.
Main outcome measured: Genomic DNA was genotyped for repeat length polymorphisms or single nucleotide polymorphisms.
Results: A significant association was identified between gender dysphoria and ERα, SRD5A2, and STS alleles, as well as ERα and SULT2A1 genotypes. Several allele combinations were also overrepresented in transgender women, most involving AR (namely, AR-ERβ, AR-PGR, AR-COMT, CYP17-SRD5A2). Overrepresented alleles and genotypes are proposed to undermasculinize/feminize on the basis of their reported effects in other disease contexts.
Conclusion: Gender dysphoria may have an oligogenic component, with several genes involved in sex hormone-signaling contributing.