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

Cortés-Cortés, Joselyn; Fernández, Rosa; Teijeiro, Nerea; Gómez‐Gil, Esther; Esteva, Isabel; Almaraz, Mari Cruz; Guillamón, Antonio; Pásaro, Eduardo

doi:10.1016/j.jsxm.2016.12.234

Cited by 23 publications

(15 citation statements)

References 38 publications

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“…On the other hand, these data are also consistent with our previous genetic data on the participation of the ESR1 gene in the genetic basis of gender dysphoria. 30,31 Here, we propose that variations in RIII methylation are related to the process of masculinization of the brain and, therefore, to the etiology of gender incongruence.…”

Section: Discussionmentioning

confidence: 99%

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

Fernández

Ramírez

Gómez‐Gil

et al. 2020

The Journal of Sexual Medicine

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Background: Brain sexual differentiation is a process that results from the effects of sex steroids on the developing brain. Evidence shows that epigenetics plays a main role in the formation of enduring brain sex differences and that the estrogen receptor a (ESR1) is one of the implicated genes. Aim: To analyze whether the methylation of region III (RIII) of the ESR1 promoter is involved in the biological basis of gender dysphoria. Methods: We carried out a prospective study of the CpG methylation profile of RIII (À1,188 to À790 bp) of the ESR1 promoter using bisulfite genomic sequencing in a cisgender population (10 men and 10 women) and in a transgender population (10 trans men and 10 trans women), before and after 6 months of gender-affirming hormone treatment. Cisgender and transgender populations were matched by geographical origin, age, and sex. DNAs were treated with bisulfite, amplified, cloned, and sequenced. At least 10 clones per individual from independent polymerase chain reactions were sequenced. The analysis of 671 bisulfite sequences was carried out with the QUMA (QUantification tool for Methylation Analysis) program. Outcomes: The main outcome of this study was RIII analysis using bisulfite genomic sequencing. Results: We found sex differences in RIII methylation profiles in cisgender and transgender populations. Cismen showed a higher methylation degree than ciswomen at CpG sites 297, 306, 509, and at the total fragment (P .003, P .026, P .001, P .006). Transmen showed a lower methylation level than trans women at sites 306, 372, and at the total fragment (P .0001, P .018, P .0107). Before the hormone treatment, transmen showed the lowest methylation level with respect to cisgender and transgender populations, whereas transwomen reached an intermediate methylation level between both the cisgender groups. After the hormone treatment, transmen showed a statistically significant methylation increase, whereas transwomen showed a non-significant methylation decrease. After the hormone treatment, the RIII methylation differences between transmen and transwomen disappeared, and both transgender groups reached an intermediate methylation level between both the cisgender groups. Clinical Implications: Clinical implications in the hormonal treatment of trans people. Strengths & Limitations: Increasing the number of regions analyzed in the ESR1 promoter and increasing the number of tissues analyzed would provide a better understanding of the variation in the methylation pattern. Conclusions: Our data showed sex differences in RIII methylation patterns in cisgender and transgender populations before the hormone treatment. Furthermore, before the hormone treatment, transwomen and

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Section: Discussionmentioning

confidence: 99%

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

Fernández

Ramírez

Gómez‐Gil

et al. 2020

The Journal of Sexual Medicine

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“…In brief, the model asserts that many genes contribute to-but do not determine-complex traits. Studies have shown that most complex traits are multifactorial and polygenic, meaning that hundreds or thousands of genetic variants, each with individually small effects, contribute additively to trait variance along with other non-genetic factors (Cortes-Cortes et al 2017;Fernandez et al 2015Fernandez et al , 2014aGratten et al 2014;Gusev et al 2013Gusev et al , 2014Shi et al 2016). This stands in contrast to monogenic or oligogenic traits in which fewer than a dozen genes account for the majority of the genetic contribution to the trait.…”

Section: The Polygenic Threshold Modelmentioning

confidence: 99%

The Biological Contributions to Gender Identity and Gender Diversity: Bringing Data to the Table

et al. 2018

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The American Psychological Association defines gender identity as, "A person's deeply-felt, inherent sense of being a boy, a man, or a male; a girl, a woman, or a female; or an alternative gender (e.g., genderqueer, gender nonconforming, gender neutral) that may or may not correspond to a person's sex assigned at birth or to a person's primary or secondary sex characteristics" (American Psychological Association, Am Psychol 70(9):832-864, 2015). Here we review the evidence that gender identity and related socially defined gender constructs are influenced in part by innate factors including genes. Based on the data reviewed, we hypothesize that gender identity is a multifactorial complex trait with a heritable polygenic component. We argue that increasing the awareness of the biological diversity underlying gender identity development is relevant to all domains of social, medical, and neuroscience research and foundational for reducing health disparities and promoting human-rights protections for gender minorities.

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“…It is widely accepted that genetic factors play key roles in the etiology of GD 1 . In recent years, the association between GD and gene polymorphismshas been investigated 8 – 13 , 25 , 26 . We investigated possible GD-associated pathogenic mutations by performing a WGS analysis of 9 FtMs and WES analysis of 4 MtFs.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates a role for genetic factors in the development of GD. A small number of candidate genes for GD have been studied, including the androgen receptor, estrogen receptor alpha, estrogen receptor beta, CYP17A1 and CYP19A1 8 – 13 . However, these results are rather mixed 4 .…”

Section: Introductionmentioning

confidence: 99%

Genomic Characteristics of Gender Dysphoria Patients and Identification of Rare Mutations in RYR3 Gene

Yang

Xiao-hai

Zhang

et al. 2017

Sci Rep

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Gender dysphoria (GD) is characterized by an incongruence between the gender assigned at birth and the gender with which one identifies. The biological mechanisms of GD are unclear. While common genetic variants are associated with GD, positive findings have not always been replicated. To explore the role of rare variants in GD susceptibility within the Han Chinese population, whole-genome sequencing of 9 Han female-to-male transsexuals (FtMs) and whole-exome sequencing of 4 Han male-to-female transsexuals (MtFs) were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level and then by Gene Ontology terms. Novel nonsynonymous variants in ion transport genes were significantly enriched in FtMs (P- value, 2.41E-10; Fold enrichment, 2.8) and MtFs (P- value, 1.04E-04; Fold enrichment, 2.3). Gene burden analysis comparing 13 GD cases and 100 controls implicated RYR3, with three heterozygous damaging mutations in unrelated FtMs and zero in controls (P = 0.001). Importantly, protein structure modeling of the RYR3 mutations indicated that the R1518H mutation made a large structural change in the RYR3 protein. Overall, our results provide information about the genetic basis of GD.

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

Cited by 23 publications

References 38 publications

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

Gender-Affirming Hormone Therapy Modifies the CpG Methylation Pattern of the ESR1 Gene Promoter After Six Months of Treatment in Transmen

The Biological Contributions to Gender Identity and Gender Diversity: Bringing Data to the Table

Genomic Characteristics of Gender Dysphoria Patients and Identification of Rare Mutations in RYR3 Gene

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