Brain, Body Incongruence in Transgenders: Gene Variants Provide Some Insights

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February  06, 2020 – Some of the first biological evidence of the incongruence transgender individuals experience, because their brain indicates they are one sex and their body another, may have been found in estrogen receptor pathways in the brain of 30 transgender individuals.

Genetic variants investigators identified may mean that in natal males (people whose birth sex is male) this critical estrogen exposure doesn’t 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 wouldn’t, leading to masculinization. Both could result in an incongruence between a person’s internal gender and their external sex. The negative emotional experience associated with this incongruence is called gender dysphoria.

Affected individuals may experiencing dysphoria because the gender they feel on the inside does not match their external sex.  Once someone has a male or female brain, important areas of the brain are programmed this way and this does not change anymore.  The goal of treatments like hormone therapy and surgery is to help their body more closely match where their brain already is.

In the present study, gene variants in pathways that are important in some of these different areas of the brain have been found. These brain pathways are involved in areas of the brain where the number of neurons and how connected the neurons are typically are different between males and females. Thus, the researchers 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. Extensive whole exome analysis, which sequences all the protein-coding regions of a gene (protein expression determines gene and cell function) was performed. The variants they found were not present in a group of 88 control exome studies in nontransgender individuals. They also were rare or absent in large control DNA databases.

As far as genes related to pathways of sexual differentiation in the brain are concerned, the researchers found, among others,  21 variants involved in 19 genes related to these pathways: AKR1C3, BOK, CDH8, CDK12, CTNNA2, DNER, DSCAML1, EGF, EFHD2, GRIN1, KCNK3, MAP4K3, PIK3CA, PPARGC1B, RIMS3, RIMS4, SPHK1, SYNPO, and TNN. These included 17 missense and 4 nonsense variants.

The exact role of all or some of these variant genes in the generation of the observed patient phenotypes is not yet fully understood, and it is certainly too early to definitively say the gene variants in these pathways definitively result in the brain-body incongruence called gender dysphoria. Nevertheless,  it is interesting that they are in pathways of hormone involvement in the brain and whether it gets exposed to estrogen or not, and that they may represent a genetic component of gender identity.

See also this short sequence on gender dysphoria:

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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