Gene variants that could play a role in the incongruence transgender individuals experience may have been found in the genes for oestrogen receptor pathways. Published in Nature, this study identified some of the first biological evidence that linked 21 gene variants in 19 genes with a possible role in sex-specific development during birth in an aim to better understand gender identity.

Gender dysphoria is the distress that a person feels due to a mismatch between their gender identity and their sex assigned at birth. It has been proposed that genetics may play a role in gender dysphoria, but none to date have been verified. Around 0.5-1.4% of individuals born male and 0.2-0.3% of individuals born female meet the criteria for gender dysphoria, and it’s more likely that identical twins report gender dysphoria than fraternal twins.

The researchers looked to oestrogen, or androgen which is converted to oestrogen in the brain, for clues on gender dysphoria. Pathways in the brain involving these hormones differ between males and females. An oestrogen bath occurs in natal males during birth to ensure masculinisation of the brain, something that isn’t well understood and hence the researchers decided to target.

13 transgender males, individuals born female and transitioning to male, and 17 transgender females, born male and transitioning to female, underwent whole exome analysis at the Yale Center for Genome Analysis and were confirmed with Sanger sequencing. 88 nontransgender individuals were used as controls.

The researchers found variants that were present in the transgender individuals but not in the controls. They further identified these variants as rare or absent in large control DNA databases, and 21 of those variants were associated with oestrogen-associated pathways in the brain.

In transgender females, the variants could affect how oestrogen is exposed in the brain at birth, meaning their brain doesn’t get masculinised. In transgender males, this could mean that oestrogen exposure happens when it normally wouldn’t and lead to masculinisation. The brain continues to develop after birth and having these key pathways and receptors in place is important for when oestrogen arrives to aid in development.

Seven years ago, the Diagnostic and Statistical Manual of Mental Disorders replaced gender identity disorder with general dysphoria, and last year the World Health Organisation said that gender incongruence is not a mental health disorder. The researchers are now studying a further 30 individuals and hope to confirm their findings of the 21 variants found to be linked to oestrogen-associated pathways in the brain and potentially identify others.