Melbourne, Victoria, AUS. Scientists have identified a significant DNA variation that they say could result in a genetic link between reduced testosterone action and male-to-female (MtF) transsexualism.

In the largest genetic study ever done of transsexuals researchers reported that the androgen receptor (AR) gene is implicated in the weakening of testosterone signals, with a corresponding under-masculinization of the brain during fetal development.


The researchers reported their findings in Biological Psychiatry, concluding that reduced androgen and androgen signalling contributes to the female gender identity of male to female transsexuals. [C1] The study is foundational and could potentially stimulate examintion of other genes that likely play a part in the birth condition.

Context

The androgen receptor (AR) gene is known to modify the effect of the male sex hormone testosterone.

The AR gene is also known as the NR3C4 (nuclear receptor subfamily 3, group C, member 4.People typically develop an inner sense of being male or female from an early age. Transsexuals however, identify with a physical sex opposite to their perceived biological sex. Decades of theorizing in the social science has fostered the public belief that transsexualism is a lifestyle choice, conditioned by such psychosocial factors as childhood trauma. However, more recent studies increasingly have shown the importance of biological factors in differentiating the mechanisms that underlie sex and gender identity.

The research team employed a strict definition of transsexuality that avoided non-biological psychosocial values when selecting the test subjects. Moreover, they applied a clear distinction between gender and sex. The current study of male-to-female (MtF) individuals focused on anomalous gender identity, where an individual's innate perspective and expectations are at variance with their anatomical sex.

The current research is part of a larger effort to study genomic associations. Such studies examine genetic variation within the human genome. Researchers identify which genes are associated with observable traits, such as blood pressure or weight, or why some people manifest a particular birth condition or disease. [C2]

Such studies require a comparison of a subject group with the condition and a control group without. If genetic variations are more frequent in the subject group, then the variations are said to be "associated." The associated genetic variations are then considered pointers to the region of the human genome where the condition resides.

Large-scale and genome-wide association studies involve rapid scans of previously-identified markers across the complete genome, or DNA sets, of a large and diverse population sample to find genetic variations associated with a particular birth condition or disease. Since the entire genome is analysed for the genetic associations, this technique allows the genetics to be investigated in a non- hypothesis-driven manner. [C2] The computational outcomes are then available for the formation of meaningful theories and rigorous hypotheses.

The current study can be considered as an important attempt to define physical and non-psychosocia) markers — used in combination with others — for a genome-wide scan.

The Androgen Receptor (AR) Gene

Professor Vincent Harley, researcher and the paper's senior author, is the Head of Molecular Genetics at the Prince Henry's Institute (PHI). He cites cell studies that show the longer version of the androgen receptor gene is measureably less efficient when communicating the testosterone message to cells. "Based on these studies, we speculate the longer version may also work less efficiently in the brain," says Harley.

Depicted at left is the crystal structure of the human androgen receptor ligand binding domain of the androgen receptor in complex with testosterone.

The AR gene is a type of nuclear receptor, activated by the DNA binding of either of the androgenic hormones (testosterone or dihydrotestosterone). As a DNA binding transcription factor, it regulates gene expression.

The androgen receptor is most closely related to the progesterone receptor — subject to blocking by higher dosages of progestins. The image is based on item 2AM9 in the Protein Data Bank (PDB), managed by the Research Collaboratory for Structural Bioinformatics (RCSB).


Methodology and Results

In the latest study, the research team compared DNA samples from 112 male-to-female (MtF) transsexuals and 258 non-transsexual male controls. The researchers looked for potential differences in three genes known to be involved in sex development, investigating associations and interactions between:

1. coding for the AR gene, an androgen receptor (CAG repeat length)
2. coding for the ERß gene, an estrogen receptor (CA repeat length), and
3. an enzyme, CYP19 gene, which converts testosterone to estrogen (TTTA repeat length).

The team then classified individuals as short or long for each gene ( polymorphism) to examine any combined effects. No interaction associations between the three genes and transsexualism were identified. No significant differences were observed for ERß and CYP19.

However, analysis of samples for the AR gene found significant differences between test subjects and a control group. The team found longer AR gene in 55.4 percent of the MtFs and 47.6 percent of the control group members (p=0.04, a small sample result that cannot be attributed to chance).

This was revealing since AR genes are critical for the development and maintenance of observable male sexual characteristics (male sexual phenotype).

The researchers concluded there is a tendency toward the longer version of the AR receptor gene, associated with less efficient testosterone signalling. "We think that these genetic differences might reduce testosterone action and under masculinise the brain during foetal development," said researcher Lauren Hare from Prince Henry's Institute (PHI) of Medical Research.

"People who come to our clinic describe how they knew they were different at a very early age, just three or four years old.

This is something that people are born with,"

— Dr. Trudy KennedyThe research team views the findings as strengthening the view that there is a biological basis for transsexuality. Lauren Hare says “We think that these genetic differences might reduce testosterone action and under masculinise the brain during foetal development.”

The researchers said the longer AR variant gene may have resulted in less effective testosterone signalling, with a decrease in the brain's testosterone levels that drives a more feminized brain and female gender identity.

The current research team asserts their physical findings support a biological basis of how gender identity develops. The research confirmed that transsexuality was not a lifestyle decision, as some had suggested, said team member, Trudy Kennedy, the director of the Gender Dysphoria Clinic at Monash University (Melbourne).

Limitations and Future Plans

Critics of the genomic association methodology generally regard it as adequate for initial and/or small-scale investigation, but too expensive on a larger scale. According to Pearson and Manolio's assessment of the technique, "the GWA approach can also be problematic because the massive number of statistical tests performed presents an unprecedented potential for false-positive results". [C2]

Professor Vincent Harley, researcher and senior author, notes that it is highly likely that other genetic factors are also involved in this form of transsexualism. Harley is the Head of Molecular Genetics at the Prince Henry's Institute (PHI). “As with all genetic association studies it will be important to replicate these findings in other populations” said Harley.

Ron Trent, a geneticist at the University of Sydney, notes that the study's numerical variations are statistically significant. However, Trent points out that "The investigators themselves point out that numbers in association studies are important and while the numbers in their study are modest, they are still potentially quite low." Jennifer Graves agrees, saying “This is still a small sample and the effects of the difference in androgen receptor are not black and white, so obviously there is much more to be done." Graves is head of the Comparative Genomics Research Group at the Australian National University (ANU) in Canberra.

For these and other reasons, further investigations are expected to employ a variety of techniques suitable for work at increasing scales (e.g., linkage analysis). Contingent on funding, the researchers plan to deploy advanced tools and methodologies and determine if the results can be replicated in a larger population and across a wider range of genes.

The research also can lead to speculation about what may occur if sufficient funding is available to conduct a large-scale and genome-wide association study of the entire transsexual population (rigorously defined).

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