Molecular Genetics of Gender Identity Disorder

为了探讨性别认同障碍（GID）的生物学机制，我分析了性激素、雄激素受体（AR）、芳香化酶（CYP19）、雌激素受体（ER α和ER β）、孕激素受体基因的候选基因。168例FTM患者（平均年龄28.3+/-7.6岁），74例MTF患者（平均年龄39.4+/-10.0岁）。健康对照276人，女性169人（28.1 +/- 6.9岁），男性106人（35.7 +/- 10.7岁）。分析了CYP19基因的（TTTA）n重复序列、ER α基因的（TA）n重复序列、ER β基因的（CA）n重复序列、AR基因的（CAG）n重复序列，以及黄体酮受体基因的5个单核苷酸多态性（rs2008112 （+311G/A）、V660L、H770H、rs572698、PROGINS （Alu插入））。我发现所有与性激素相关的基因都与性别认知障碍症无关。然后，根据动物实验选择了其他候选基因，如e，g, Xist, Uspqy, Rps4y, DDx3y，这些基因在胎儿大脑中的表达在男性和女性之间存在很大差异，可能涉及性别认同和行为。利用NCBI数据库检索这些基因的人类同源基因和snp。分析NCBI SNP数据库中已知频率的Uspqy、Rps4y、DDx3y基因的所有SNP和Xiest基因的5个SNP。在日本人群中发现Uspqy、Rps4y和DDx3y基因的SNP均为单态。同样，Xiest基因的3个snp （C43G、rs1009948、rs1794213、rs11554116）也是单态的。对其余2个snp （rs1894271和rs1620574）进行分析。FTM患者与女性之间、MTF与男性之间的等位基因和基因型分布无显著差异。这些发现可能表明，其他未知基因可能参与GIF的发展。因此，需要进行全基因组关联研究或cDNA基因芯片分析，以鉴定GID的分子，进一步了解GID的神经机制。

To investigate the biological mechanism of gender identity disorders (GID), I analyzed candidate genes of sex hormone, androgen receptor (AR), aromatase (CYP19), estrogene receptor (ER α and ER β), progesterone receptor gene. Subjects were 168 FTM patients (average age 28.3+/-7.6), 74 MTF patients (average age 39.4+/-10.0). Healthy controls were 276 people, 169 women (28.1 +/- 6.9 years old), 106 men (35.7 +/- 10.7 years old). The (TTTA)n repeat of the CYP19 gene, (TA)n repeat of the ER α gene, (CA)n repeat of the ER β gene, (CAG)n repeat of the AR gene, five single nucleotide polymorphism (SNP) (rs2008112 (+311G/A), V660L, H770H, rs572698, PROGINS (Alu insertion)) of the progesterone receptor gene were analyzed. I found that all the sex hormone-related genes examined did not associated with GID.Then, other candidate genes, e,g, Xist, Uspqy, Rps4y, DDx3y genes were selected based on animal studies that revealed expression in the fetal brain of these genes showed great difference between male and female, which may implied involvement in sexual identity and behaviors. Human orthologs of these genes were searched using NCBI database and those SNPs. All SNPs of Uspqy, Rps4y, DDx3y genes and 5 SNPs of the Xiest gene with known allele frequency registered in NCBI SNP database were analyzed. We found any SNP of Uspqy, Rps4y and DDx3y gene was monomorphism in Japanese population. Similarly, 3 SNPs of the Xiest gene (C43G, rs1009948, rs1794213, rs11554116) were also monomorphic. Remaining 2 SNPs of the Xiest gene, rs1894271 and rs1620574, were analyzed There was no significant diffrence of allelic and genotypic distribution between FTM patients and women, and between MTF and men. These findings may suggest that the other unknown genes may be involved in development of GIF. Therefore, genome-wide association study or gene-chip analysis of cDNA should be needed for identification of molecules of GID and further understanding of neural mechanisms of GID.