Original Research
Transgender Health
Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria

https://doi.org/10.1016/j.jsxm.2016.12.234Get rights and content

Abstract

Introduction

Gender dysphoria, a marked incongruence between one's experienced gender and biological sex, is commonly believed to arise from discrepant cerebral and genital sexual differentiation. With the discovery that estrogen receptor β is associated with female-to-male (FtM) but not with male-to-female (MtF) gender dysphoria, and given estrogen receptor α involvement in central nervous system masculinization, it was hypothesized that estrogen receptor α, encoded by the ESR1 gene, also might be implicated.

Aim

To investigate whether ESR1 polymorphisms (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 and their haplotypes are associated with gender dysphoria in adults.

Methods

Molecular analysis was performed in peripheral blood samples from 183 FtM subjects, 184 MtF subjects, and 394 sex- and ethnically-matched controls.

Main Outcome Measures

Genotype and haplotype analyses of the (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 polymorphisms.

Results

Allele and genotype frequencies for the polymorphism XbaI were statistically significant only in FtM vs control XX subjects (P = .021 and P = .020). In XX individuals, the A/G genotype was associated with a low risk of gender dysphoria (odds ratio [OR] = 0.34; 95% CI = 0.16–0.74; P = .011); in XY individuals, the A/A genotype implied a low risk of gender dysphoria (OR = 0.39; 95% CI = 0.17–0.89; P = .008). Binary logistic regression showed partial effects for all three polymorphisms in FtM but not in MtF subjects. The three polymorphisms were in linkage disequilibrium: a small number of TA repeats was linked to the presence of PvuII and XbaI restriction sites (haplotype S-T-A), and a large number of TA repeats was linked to the absence of these restriction sites (haplotype L-C-G). In XX individuals, the presence of haplotype L-C-G carried a low risk of gender dysphoria (OR = 0.66; 95% CI = 0.44–0.99; P = .046), whereas the presence of haplotype L-C-A carried a high susceptibility to gender dysphoria (OR = 3.96; 95% CI = 1.04–15.02; P = .044). Global haplotype was associated with FtM gender dysphoria (P = .017) but not with MtF gender dysphoria.

Conclusions

XbaI-rs9340799 is involved in FtM gender dysphoria in adults. Our findings suggest different genetic programs for gender dysphoria in men and women.

Cortés-Cortés J, Fernández R, Teijeiro N, et al. Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria. J Sex Med 2017;14:464–472.

Introduction

Transsexualism in the International Classification of Diseases, Tenth Revision (ICD-10),1 gender identity disorder in adolescents and adults in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR),2 gender dysphoria (GD) in adolescents and adults in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),3 or gender incongruence in the future International Classification of Diseases, Eleventh Revision4 is characterized by a marked incongruence between one's experienced gender and biological sex.1, 5

The etiology is complex, but some hypotheses suggest that GD arises from discrepant cerebral and genital sexual differentiation.6 Biological and environmental factors contribute to gender identity,7, 8, 9 but increasing evidence supports the idea of genetic vulnerability. Henningsson et al10 found significant differences when they examined estrogen receptor (ER) β in a male-to-female (MtF) population. They suggested that a long ERβ polymorphism is more common in the MtF population. Hare et al11 also examined an MtF population and found a significant association between the androgen receptor and GD. Moreover, Ujike et al,12 in a Japanese population of female-to-male (FtM) and MtF subjects, found no significant differences for any examined polymorphism (androgen receptor, ERα, ERβ, cytochrome P450 2C19, and progesterone receptor). Sosa et al13 did not find significant differences when they studied the relation between long-term estrogen administration and ERα in an MtF population.

Our group analyzed the same polymorphisms and found an association between ERβ and GD in FtM subjects14 but not in MtF subjects.15

Estrogens regulate many physiologic processes, including normal cell growth, development, and tissue-specific gene regulation in the reproductive tract and central nervous system.16, 17, 18 The biological actions of estrogens are mediated by binding to one of two specific ERs, ERα or ERβ, which belong to the nuclear receptor superfamily of ligand-regulated transcription factors.16 Once bound by estrogens, the ER undergoes a conformational change leading to dimerization (homodimer ERα-α, homodimer ERβ-β, or heterodimer ERα-β), allowing the receptor to interact with high affinity with specific DNA sequences (ERE) located in or near promoter regions of target genes19, 20 and thereby modulate the transcription process.21, 22, 23, 24

The two ERs are products of different genes from different chromosomes,25, 26 exhibit different estrogen-binding affinities,27 and have distinct transcriptional properties. In the absence of the α or the β receptor, the other ER mediates the effects of estrogen on gene transcription.18 However, when the two ERs are coexpressed, they normally form the ERα-β heterodimer in which ERβ inhibits ERα transcriptional activity.18 Moreover, characterization of mice lacking ERα and/or ERβ has demonstrated that ERα is primarily involved in masculinization and ERβ has a major role in defeminization of sexual behaviors.28

Because our previous data pointed to the involvement of ERβ in GD14 and ERα is primarily involved in central nervous system masculinization,28 we suspected ERα would be involved in GD.

Therefore, the purpose of this study was to investigate the implication of ERα, encoded by gene ESR1, in GD through a molecular analysis of three polymorphisms: (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799.

Section snippets

Subjects

The sample was composed of 367 gender dysphoric volunteers (183 FtM and 184 MtF subjects) recruited through the Andalusian Gender Identity Unit (Carlos Haya Hospital, Málaga, Spain) and the Gender Identity Unit of Cataluña (Clinic Hospital of Barcelona, Barcelona, Spain). All subjects were diagnosed with transsexualism (code F64.0) according to the ICD-101 or with gender identity disorder in adolescents or adults (code 302.85) according to the DSM-IV-TR.2 The patients were examined by an

Results

The genotype frequencies for the (TA)n, PvuII, and XbaI polymorphisms were in Hardy-Weinberg equilibrium (P = .38, P = .08, and P = .24, respectively).

Discussion

Results showed an association between ERα and FtM GD. The XbaI-rs9340799 allele, genotype, and haplotype frequencies differed significantly between the FtM and control XX groups.

The observation that genotype A/G was more frequent in the control XX group than in the FtM group suggests that this XbaI heterozygote genotype favored a cerebral feminization process. In contrast, genotype A/A was more frequent in the control XY group than in the MtF group, suggesting that this second genotype favored

Conclusions

Our results suggest that polymorphism XbaI-rs9340799 and the haplotypes L-C-G and L-C-A are associated with FtM GD in adults. Our findings also suggest different genetic programs for FtM and MtF individuals, but the result of this study must be confirmed by meta-analysis given our small sample.

Statement of authorship

Category 1

  1. (a)

    Conception and Design

    • Rosa Fernández; Esther Gómez-Gil; Isabel Esteva; Antonio Guillamón; Eduardo Pásaro

  2. (b)

    Acquisition of Data

    • Joselyn Cortés-Cortés; Rosa Fernández; Nerea Teijeiro; Esther Gómez-Gil; Isabel Esteva; Mari Cruz Almaraz

  3. (c)

    Analysis and Interpretation of Data

    • Rosa Fernández; Esther Gómez-Gil; Isabel Esteva; Mari Cruz Almaraz; Antonio Guillamón; Eduardo Pásaro

Category 2
  1. (a)

    Drafting the Article

    • Joselyn Cortés-Cortés; Rosa Fernández; Nerea Teijeiro; Esther Gómez-Gil; Isabel Esteva; Mari Cruz Almaraz; Antonio

Acknowledgments

We are grateful to the patients and controls who participated in the study. We also are grateful to all the people who contributed to this work.

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      Genomic DNA was extracted from EDTA blood samples using the DNeasy Blood & Tissue Kit from Qiagen (Madrid, Spain). Polymorphisms were selected for study on the basis of their known implication in the development of cerebral sex differences in humans (Raznahan et al., 2010) and had already been studied by ourselves and others (Henningsson et al., 2005; Hare et al., 2009; Ujike et al., 2009; Fernández et al., 2014a,b, 2016; Cortés-Cortés et al., 2017). The polymorphisms selected for each gene were as follows, for the ESR2 gene: (CA)n-ERβ (rs113770630); for the ESR1 gene: XbaI-ERα (rs9340799); for the AR gene: (CAG)n-AR (rs193922933); and for the aromatase CYP19A1 gene: (TTTA)n-CYP19A1 (rs60271534) (Supplemental Figure S1).

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    Conflicts of Interest: The authors report no conflicts of interest.

    Funding: This work was supported by grants PSI2010-15115 (to E.P.) and PSI2014-58004-P (to A.G.).

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