title: Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria.
abstract: 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.
  
  
  
  To investigate whether ESR1 polymorphisms (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 and their haplotypes are associated with gender dysphoria in adults.
  
  
  
  Molecular analysis was performed in peripheral blood samples from 183 FtM subjects, 184 MtF subjects, and 394 sex- and ethnically-matched controls.
  
  
  
  Genotype and haplotype analyses of the (TA)n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 polymorphisms.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Departamento de Psicología, Área Psicobiología, Universidade da Coruña, A Coruña, Spain.
authors.forename: Joselyn
authors.initials: J
authors.lastname: Cortés-Cortés
authors.affiliation: Departamento de Psicología, Área Psicobiología, Universidade da Coruña, A Coruña, Spain. Electronic address: rosa.fernandez@udc.es.
authors.forename: Rosa
authors.initials: R
authors.lastname: Fernández
authors.affiliation: Departamento de Psicología, Área Psicobiología, Universidade da Coruña, A Coruña, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Teijeiro
authors.affiliation: Unidad de Identidad de Género, Hospital Clinic, Barcelona, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Gómez-Gil
authors.affiliation: Unidad de Transexualidad e Identidad de Género, Hospital Carlos Haya, Málaga, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Esteva
authors.affiliation: Unidad de Transexualidad e Identidad de Género, Hospital Carlos Haya, Málaga, Spain.
authors.forename: Mari Cruz
authors.initials: MC
authors.lastname: Almaraz
authors.affiliation: Departamento de Psicobiología, UNED, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Guillamón
authors.affiliation: Departamento de Psicología, Área Psicobiología, Universidade da Coruña, A Coruña, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Pásaro
mesh_terms: D000328:Adult; D000483:Alleles; D047628:Estrogen Receptor alpha / Q000235:genetics*; D005260:Female; D000068116:Gender Dysphoria / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D011110:Polymorphism, Genetic
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha
keywords: Estrogen Receptor α; Estrogen Receptor β; Gender Dysphoria; rs2234693; rs3138774; rs9340799