Elsevier

Biological Psychiatry

Volume 65, Issue 1, 1 January 2009, Pages 93-96
Biological Psychiatry

Brief Report
Androgen Receptor Repeat Length Polymorphism Associated with Male-to-Female Transsexualism

https://doi.org/10.1016/j.biopsych.2008.08.033Get rights and content

Background

There is a likely genetic component to transsexualism, and genes involved in sex steroidogenesis are good candidates. We explored the specific hypothesis that male-to-female transsexualism is associated with gene variants responsible for undermasculinization and/or feminization. Specifically, we assessed the role of disease-associated repeat length polymorphisms in the androgen receptor (AR), estrogen receptor β (ERβ), and aromatase (CYP19) genes.

Methods

Subject-control analysis included 112 male-to-female transsexuals and 258 non-transsexual males. Associations and interactions were investigated between CAG repeat length in the AR gene, CA repeat length in the ERβ gene, and TTTA repeat length in the CYP19 gene and male-to-female transsexualism.

Results

A significant association was identified between transsexualism and the AR allele, with transsexuals having longer AR repeat lengths than non-transsexual male control subjects (p = .04). No associations for transsexualism were evident in repeat lengths for CYP19 or ERβ genes. Individuals were then classified as short or long for each gene polymorphism on the basis of control median polymorphism lengths in order to further elucidate possible combined effects. No interaction associations between the three genes and transsexualism were identified.

Conclusions

This study provides evidence that male gender identity might be partly mediated through the androgen receptor.

Section snippets

Participants

One hundred and twelve Caucasian male-to-female transsexuals, pre- and post-operative, were recruited from Monash Medical Centre (MMC), Victoria, Australia (n = 76) and from University of California, Los Angeles (UCLA) (n = 36) as per criteria in the DSM-IV—some of whom had reports of gender dysphoria in childhood. Almost all transsexual individuals were receiving hormone treatment. Two hundred and fifty-eight Caucasian male control subjects were also recruited from MMC. Ethical approvals for

Results

Polymorphic fragment lengths for 258 male subjects and 112 transsexuals were obtained. Twenty-one different alleles were identified for the AR gene polymorphism, 14 for the ERβ gene polymorphism, and 8 for the CYP19 gene polymorphism. The percentages of each allele in the control and transsexual populations are shown in Figure 1. For the AR gene, a difference in the mean repeat length was identified, with transsexuals having significantly longer mean repeat lengths (243.2 base pairs) than

Discussion

To date, this is the largest genetic study of transsexualism conducted. We observed a significant association between longer AR gene polymorphisms and male-to-female transsexualism. Longer CAG repeats in the AR gene lead to reduced binding of the AR protein to co-activator, due to its inhibitory interaction with the receptor, resulting in less effective testosterone signalling (19), a mechanism typically involved in masculinization of the brain during early development (1). Female subjects

References (20)

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