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Exploring the Genetic Contribution to Incongruence Between an Individual's Internal Gender and External Sex

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A recent study by scientists at the Medical College of Georgia at Augusta University explored the contribution of genetics to our gender identity. The research identified 21 variants in 19 genes in estrogen signaling pathways of the brain. These pathways are implicated in regions of the brain where the quantity of neurons and the neuronal connections often differ between males and females.

Through their work, the scientists aim to better understand the biological contribution to the spectrum of gender identities and challenge the notion that narrative that gender is a choice.

Technology Networks spoke with John Graham Theisen, MD, senior author of the study, to learn more about the study and the researchers' next steps in this space.

Molly Campbell (MC): Your research focuses include the genetic contribution to gender identity. Can you tell us more about the history of this area of research?

John Graham Theisen (JGT):
Over the course of the last twenty years, there has been an increasing interest within the scientific community in understanding the biologic contribution to gender identity, and there is evidence from twin studies that at least a portion of that biologic contribution is genetic. During roughly that same timeframe, the cost of whole genome and whole exome sequencing rapidly started to diminish and become more accessible to researchers throughout the world. Those new methods have allowed teams like ours to gain a better understanding of the genetic component of complex human traits, because they allow researchers to evaluate all the variants in individuals’ genomes as opposed to having to look at just a few.

Our experiences with our transgender patients, and the fact that many of them knew as early as five years old that their external sex and internal sense of gender didn’t match, combined with the prior evidence that there is likely a genetic contribution to gender dysphoria, led us to begin our search for what that contribution was.

MC: What are your goals and aims in this research space?

The primary goal of our research is to gain a better understanding of the biologic component contributing to the spectrum of gender identities, and thus help our patients to gain a better understanding of themselves. Beyond that, we believe that with this enhanced understanding, we will be able to counter the discriminatory narrative that gender identity is a choice.

MC: You previously said “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," – Please can you expand on what is meant by a "masculine" or "feminine" brain?

Essentially, this refers to areas of the brain where the number of neurons, or the density of the connections between neurons, is different when comparing males and females. In some areas of the brain, these metrics are higher in females, while in others they are higher in males, and in animal models, these differences have been linked to sex-specific behavior.

MC: Please can you tell us about the study published in Scientific Reports and your key findings with regards to the twenty-one variants in 19 genes?

Our team evaluated the exomes of 30 transgender individuals and confirmed 21 variants in 19 genes that had previously been associated with estrogen driven pathways of sex-specific neurodevelopment. Each of the confirmed variants was extremely rare, occurring at a rate of less than 0.01 in the general population, and each variant was predicted to be among the top 0.1% in the genome to cause a functional change when compared to wild-type. We presented these findings as part of a larger framework for conducting research into the genetic contribution to gender identity.

MC: Can you tell us more about why the results of the study were published as preliminary?

We consider these results preliminary because they are based on findings from a relatively small sample size of 30 individuals. To address this, we are continuing to enroll as many patients as possible, with a goal of enrolling at least 200 people in total.

MC: What are your next steps taking the research forward?

Right now, there are four areas that we are working on.First, we continue to enroll new patients, and then add the information from their exome sequencing to our growing body of information. The more people we enroll, the clearer the findings become. Second, we are working on new statistical models to help us determine the significance of variants found in families of genes in addition to variants in single genes. Third, for some of our most promising initial results, we are beginning the next steps in testing, which is in-vitro functional analysis. This is critical to understanding if a variant in a gene has the effect that you predict that it will.

Finally, we think that it is imperative that genetic research involving the transgender community incorporates the attitudes, opinions, and beliefs that exist within that community into the design and planning of the research itself. For that reason, we are conducting an online survey study that is assessing those exact opinions.

John Graham Theisen, MD, was speaking to Molly Campbell, Science Writer, Technology Networks.

Reference: Theisen et al. (2020). The Use of Whole Exome Sequencing in a Cohort of Transgender Individuals to Identify Rare Genetic Variants. Scientific Reports. DOI: https://doi.org/10.1038/s41598-019-53500-y.