New research has identified gene variants found only in the brains of transgender individuals. These genes are primarily involved in estrogens critical sprinkling of the brain right before or after birth, which is essential to masculinization of the brain.

The study, which included 13 transgender males (female to male) and 17 transgender females (male to female), reveals some of the first biological evidence of the incongruence transgender people experience because their brain indicates they are one sex and their body another.

Twenty-one variants in 19 genes have been found in estrogen signaling pathways of the brain critical to establishing whether the brain is masculine or feminine, says Dr. J. Graham Theisen, obstetrician/gynecologist and National Institutes of Health Womens Reproductive Health Research Scholar at the Medical College of Georgia at Augusta University.

In natal males (people whose birth sex is male), this critical estrogen exposure doesnt happen, or the pathway is altered so the brain does not get masculinized. In natal females, it may mean that estrogen exposure happens when it normally wouldnt, leading to masculinization.

Both could result in an incongruence between a persons internal gender and their external sex. The negative emotional experience associated with this incongruence is called gender dysphoria.

They are experiencing dysphoria because the gender they feel on the inside does not match their external sex, Theisen says. Once someone has a male or female brain, they have it and you are not going to change it. The goal of treatments like hormone therapy and surgery is to help their body more closely match where their brain already is.

The findings are published in the journal Scientific Reports.

It doesnt matter which sex organs you have, its whether estrogen, or androgen, which is converted to estrogen in the brain, masculinizes the brain during this critical period, says Dr. Lawrence C. Layman, chief of the MCG Section of Reproductive Endocrinology, Infertility and Genetics in the Department of Obstetrics and Gynecology. We have found variants in genes that are important in some of these different areas of the brain.

While its too early to definitively say the gene variants in these pathways result in the brain-body incongruence called gender dysphoria, it is interesting that they are in pathways of hormone involvement in the brain and whether it gets exposed to estrogen or not, says Layman.

This is the first study to lay out this framework of sex-specific development as a means to better understand gender identity, Theisen says. We are saying that looking into these pathways is the approach we are going to be taking in the years ahead to explore the genetic contribution to gender dysphoria in humans.

For the study, the team looked at the DNA of 13 transgender males, individuals born female and transitioning to male, and 17 transgender females, born male and transitioning to female.

The extensive whole exome analysis was conducted at the Yale Center for Genome Analysis.The variants found were not present in a group of 88 control exome studies in nontransgender individuals also done at Yale. They also were rare or absent in large control DNA databases.

Reproductive endocrinologist/geneticist Layman says his 20 years of experience taking care of transgender patients made him think there was a biological basis. We certainly think that for the majority of people who are experiencing gender dysphoria there is a biologic component, says Theisen. We want to understand what the genetic component of gender identity is.

Although genetics have been suggested as a factor in gender dysphoria, proposed candidate genes to date have not been verified, the researchers say. Most gene or gene variants previously investigated have been linked to receptors for androgens, hormones more traditionally thought to play a role in male traits but, like estrogen in males, are also present in females.

The team decided instead to take what little is known about sex-specific brain development that estrogen bath needed in early life to ensure masculinization of the brain to hone in on potential sites for relevant genetic variances.

Extensive DNA testing initially revealed more than 120,000 variants, 21 of which were associated with these estrogen-associated pathways in the brain.

Theisen notes that we all are full of genetic variants, including ones that give us blue eyes versus brown or green, and the majority do not cause disease, but rather help make us individuals. I think gender is as unique and as varied as every other trait that we have, Theisen says.

The investigators suggest modification of the current system for classifying variants that would not imply that a variant means pathogenic (disease causing).

Last year, the World Health Organization said that gender incongruence is not a mental health disorder and six years before that, the Diagnostic and Statistical Manual of Mental Disorders replaced gender identity disorder with general dysphoria.

About 0.5 to 1.4% of individuals born male and 0.2 to 0.3% of individuals born female meet criteria for gender dysphoria. Identical twins are more likely than fraternal twins to both report gender dysphoria.

Gender affirming therapies, like hormone therapies and surgeries, along with mental health evaluation and support help these individuals better align their bodies and brains, the scientists say.

Source: Medical College of Georgia at Augusta University

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