ORIGINAL RESEARCH Analysis of Four Polymorphisms Located at the Promoter of the Estrogen Receptor Alpha ESR1 Gene in a Population With Gender Incongruence Rosa Fernández, PhD, 1,2 Enrique Delgado-Zayas, Pre-doc, 1,2 Karla Ramírez, Pre-doc, 1,2 Joselyn Cortés-Cortés, PhD, 1,2 Esther Gómez-Gil, MD, 3 Isabel Esteva, MD, 4 Mari Cruz Almaraz, MD, 4 Antonio Guillamon, MD, 5 and Eduardo Pásaro, PhD 1,2 ABSTRACT Introduction: Gender incongruence defines a state in which individuals feel discrepancy between the sex assigned at birth and their gender. Some of these people make a social transition from male to female (trans women) or from female to male (trans men). By contrast, the word cisgender describes a person whose gender identity is consistent with their sex assigned at birth. Aim: To analyze the implication of the estrogen receptor a gene (ESR1) in the genetic basis of gender incongruence. Main Outcome Measures: Polymorphisms rs9478245, rs3138774, rs2234693, rs9340799. Method: We carried out the analysis of 4 polymorphisms located at the promoter of the ESR1 gene (C1 ¼ rs9478245, C2 ¼ rs3138774, C3 ¼ rs2234693, and C4 ¼ rs9340799) in a population of 273 trans women, 226 trans men, and 537 cis gender controls. For SNP polymorphisms, the allele and genotype fre- quencies were analyzed by c 2 test. The strength of the SNP associations with gender incongruence was measured by binary logistic regression. For the STR polymorphism, the mean number of repeats were analyzed by the ManneWhitney U test. Measurement of linkage disequilibrium and haplotype frequencies were also performed. Results: The C2 median repeats were shorter in the trans men population. Genotypes S/S and S/L for the C2 polymorphism were overrepresented in the trans men group (P ¼ .012 and P ¼ .003 respectively). We also found overtransmission of the A/A genotype (C4) in the trans men population (P ¼ .017), while the A/G genotype (C4) was subrepresented (P ¼ .009]. The analyzed polymorphisms were in linkage disequilibrium. In the trans men population, the T(C1)-L(C2)-C(C3)-A(C4) haplotype was overrepresented (P ¼ .019) while the T(C1)-L(C2)-C(C3)-G(C4) was subrepresented (P ¼ .005). Conclusion: The ESR1 is associated with gender incongruence in the trans men population. Fernández R, Delgado-Zayas E, Ramírez K, et al. Analysis of Four Polymorphisms Located at the Promoter of the Estrogen Receptor Alpha ESR1 Gene in a Population With Gender Incongruence. Sex Med 2020;XX:XXXeXXX. Copyright Ó 2020, The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Key Words: Gender incongruence; transgender; rs9478245; rs3138774; rs2234693; rs9340799 Received December 30, 2019. Accepted April 5, 2020. 1 Centro de Investigaciones Científicas Avanzadas (CICA), Departamento de Psicología. Universidade da Coruña (UDC), Campus de Elviña, A Coruña, Spain; 2 Instituto de Investigación Biomédica de A Coruña (INIBIC), CHUAC, SER- GAS, A Coruña, Spain; 3 Unidad de Identidad de Género, Instituto de Neurociencias, Hospital Clínic, I.D.I.B.A.P.S, Barcelona, Spain; 4 Servicio de Endocrinología y Nutrición, Unidad de Identidad de Género del Hospital Regional Universitario de Málaga, Málaga, Spain; 5 Departamento de Psicobiología, Universidad Nacional de Educación a Distancia, Madrid, Spain Copyright ª 2020, The Authors. Published by Elsevier Inc. on behalf of the International Society for Sexual Medicine. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). https://doi.org/10.1016/j.esxm.2020.04.002 Sex Med 2020;-:1e11 1