Genetic Link Between Gender Dysphoria and Sex Hormone Signaling

Madeleine Foreman; Lauren Hare; Kate York; Kara Balakrishnan; Francisco J. Sánchez; Fintan Harte; Jaco Erasmus; Eric Vilain; Vincent R. Harley


J Clin Endocrinol Metab. 2019;104(2):390-396. 

In This Article

Abstract and Introduction


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.


Gender identity—our sense of being male or female— develops early in life. By age 2 years, most children are able to identify their own gender, which is typically consistent with the sex they were at birth.[1,2] Yet, a small percentage of people will report substantial clinical distress because their sex at birth does not reflect their gender identity.[3] In extreme cases, patients will be given the diagnosis of gender dysphoria and may undergo medical treatments to better align their anatomy and physiology with their gender identity.

Many identity labels may be used among this group of people, with transgender being a broad, encompassing term for many subtypes. In this report, we focus on transgender women, or people whose sex was male at birth and who later transitioned to be female (historically referred to as male-to-female transsexual). Unlike other people who may be transgender, transgender women take steps to affirm their gender identity by social and/or physical transitioning from their birth sex to their experienced gender through cross-hormone treatment and surgery.[4]

The etiology of gender dysphoria is unknown, yet the reported prevalence has been increasing, with most estimates suggesting that as many as 521 in 100,000 males and 265 in 100,000 females experience gender dysphoria.[5] Early research into gender dysphoria focused on the belief that it was a psychological condition and suggested that dysfunctional family dynamics[6] and traumatic childhood experiences[7] may contribute to gender dysphoria. However, recent studies point toward a biological basis involving endocrine, neurobiological and genetic factors. For instance, an increased prevalence of gender dysphoria was observed among people who experienced atypical prenatal androgen exposure in utero, such as females with congenital adrenal hyperplasia.[8–15] Neuroimaging studies revealed specific regions in the brains of transgender women that may be more similar to the brains of women serving as control subjects (than that of men serving as control subjects.[16–18] Heritability studies suggest a genetic component: 23% to 33% of monozygotic twin pairs are concordant for gender dysphoria.[19]

Candidate gene association studies have begun to investigate whether functional variants in sex hormone– signaling genes are associated with gender dysphoria. It is proposed that functional variants may alter sex hormone signaling, causing atypical sexual differentiation of the developing brains of those who will later experience gender dysphoria.[20] Some associations have been identified, including an overrepresentation of long CAG repeats in the AR of transgender women[21] and an overrepresentation of the CYP17 T/C SNP,[22,23]ERβ CA repeat,[24] and ERα Xbal A/G single nucleotide polymorphism (SNP)[25] in transgender men. Other studies found no associations.[26–28] Most studies have been limited by small sample sizes and there is a need to reproduce findings in large, independent cohorts.

We hypothesized that gender dysphoria in transgender women is associated with genetic variants in sex hormone– signaling genes responsible for undermasculinization and/or feminization of the brain. The aim of our study was to conduct a genetic association study of 12 sex signaling genes, including COMT, CYP11A1, HSD17B6, STS, and SULT2A1, which, to our knowledge, have not previously been studied in the context of gender dysphoria. We determined the allele and genotype frequencies of variable polymorphic lengths of seven genes and SNPs of five genes in Caucasian (non-Latino) transgender women and compared these with Caucasian (non-Latino) male control subjects.