Poster Presentation ESA-SRB-APEG-NZSE 2022

Exploring Potential Genetic Contributions to Gender Incongruence (#268)

Blake Ashley 1 , Vincent Harley 1
  1. Hudson Institute of Medical Research, Melbourne, VIC, Australia

Gender Incongruence (GI) is a marked and persistent incongruence between an individual’s gender and their chromosomal/anatomical sex. Individuals who identify as a member of the opposite sex are known as transgender. Twin studies suggest there is a substantial heritable component to GI, but the genetic mechanisms are currently unknown. Efforts to identify specific genetic contributions have focussed on the hypothesis that variation in sex steroidogenesis genes in those who experience GI may alter the sexual differentiation of neuroanatomy. Candidate gene studies have investigated whether variants in sex steroidogenesis genes are overrepresented in transgender individuals. Here, we aimed to investigate the potential genetic contribution to GI with two methods. Firstly, we conducted a meta-analysis of candidate gene studies in transgender individuals. Of five genes in the sex steroidogenesis pathway (androgen receptor, estrogen receptor alpha and beta, aromatase, and CYP17), meta-analysis confirmed a significant association between variants in ESR1 (p = 0.0077) and GI amongst natal males (n = 670 transgender women, 669 cisgender men). Secondly, we conducted the first genome-wide association study in transgender individuals. Although no significant associations were identified in this preliminary study (n = 52 transgender women, 84 cisgender controls), the most associated SNP (p = 1.738 x 10-5) was in HDAC9, a global regulator of transcription. HDAC9 plays a crucial role in the development of sexually dimorphic regions of the brain that regulate sex steroidogenesis and sexual behaviour, and which have been shown to be altered in transgender individuals. By studying the mechanisms by which GI occurs, we also implicitly study how gender identity develops. These preliminary results suggest that variants in genes involved in governing sex steroidogenesis and sexual brain differentiation may contribute to GI, and thus, that gender identity may develop out of the sexual differentiation of the brain.