Abstract

Gender dysphoria(GD),a marked incongruence between one’s experienced gender and biological sex, is commonly believed to arise from discrepant cerebraland genital sexual differentiation. Biological and environmental factors (deregulation of sex hormone levels during earl feta development) contributet o GD,but increasing evidence also supports the idea of genetic vulnerability. Our grouppreviouslyfoundanassociationbetweenestrogen receptor (ER) β andGD (Fernándezetal.,2014a-b).Estrogens regulate man yphysiological processes by binding to their specific estrogen receptors, α or β, which belong to the family of ligand-regulated transcription factors.Once bound by estrogens, the ER undergoes a conformational change allowing it to interact with high affinity with specific DNA sequences located in o rnear promoter regions of awide set of target genes and modulating the transcription of multiple genes in a cascade process (Yang&Shah, 2014). Aim: To investigate the implication of polymorphism ERα-XbaI rs9340799 inGD. Methods: Analysis was performed in blood samples from 426 female-to-males(FtMs),588 male-to-females (MtFs) and1327 sex and ethnically-matched controls.The sample was recruited through the Andalucía Gender Identity Unit (Carlos Haya Hospital of Málaga,Spain) and the Gender Identity Unit of Cataluña (Clínic Hospital of Barcelona,Spain). All subjects were diagnosed withTranssexualism (F64.0) according to the ICD-10 or with Gender Identity Disorder in Adolescents or Adults (302.85) according to the DSM-IV-TR. The control groups consisted of two random groups of individuals diagnosed as not having GD,previously used inmetabolic and genetic studies,who were pair-matched for chromosomal sex, ethnicity and geographical origin. The exclusion criteria were head trauma,neurological disorder, and history of alcohol and/or drug abuse. a.MolecularAnalysis Genomic DNA was extracted from EDTA blood samples using the DNeasy Blood &Tissue Kit from Qiagen.The ERα-XbaI polymorphism was analyzed by PCR-RFL Pas suggested by vanMeurs(2003). Absence of restriction sites was specified as G,and the resulting genotypes were G/G ,A/G,and A/A b.Statistical methods The analyses were performed using SPSS®23.0witha p b 0.05 as significant, and by the free online software SNPStats http:// bioinfo.iconcologia.net/SNPstats Results: The genotype frequencies were in Hardy-Weinberg equilibrium. The allele and genotype frequencies for the ERα-XbaI polymorphism were significantly different between FtM and XX control group(χ2 = 4.049; p = 0.044and χ2 = 11.237; p = 0.004) but not significantly different between the MtF and XY control group (χ2=2.686; p=0.101and χ2=5.366; p=0.068). The interaction analysis with the chromosomal sex covariate showed that genotype A/G has aprotective effect for biological females [OR=0.38(0.21-0.67) p=0.00031] while the same genotype has a high risk effect for biological males[OR=1.92(1.10-3.34)); p=0.00031]. Conclusion: According to our data,and in conjunction wit hour previous work, both ERα and β are implicated in the etiology of GD. Our results suggest that genotype A/G favored cerebral feminization being aprotective effect to the biological females and a risk effect for biological males.And a larger number of repeat sin ERβ promotes a cerebral defeminization process. doi:10.1016/j.jpsychores.2017.03.238