Molecular Genetics of Gender Identity Disorder

为了探讨性别认同障碍的生物学机制，我分析了性激素的候选基因，雄激素受体(AR)、芳香酶19、雌激素受体(ERα和ERβ)、孕激素受体基因。受试者为FTM患者168例，平均年龄28.3±-7.6岁，MTF患者74例，平均年龄39.4±10.0岁。健康对照组276人，女性169人(28.1+/-6.9岁)，男性106人(35.7+/-10.7岁)。分析细胞色素P19基因(TTTA)n重复、ERα基因(TA)n重复、ERβ基因(CA)n重复、AR基因(CAG)n重复、孕激素受体基因5个单核苷酸多态(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GID无关。然后，根据动物研究筛选出其他候选基因，如Xist，Uspqy，Rps4y，DDx3y，这些基因在胎脑中的表达显示出性别差异，这可能表明这些基因参与了性别认同和行为。使用NCBI数据库和这些SNPs搜索这些基因的人类同源基因。对NCBI SNP数据库中已知等位基因频率的Uspqy、Rps4y、DDx3y基因的全部SNPs和XIEST基因的5个SNPs进行分析。我们发现Uspqy、Rps4y和DDx3y基因的任何SNP在日本人群中都是单态的。同样，XIST基因的3个SNP(C43G、rs1009948、rs1794213、rs11554116)也是单态的。对其余2个XEST基因的SNPs，rs1894271和rs1620574进行分析，发现FTM患者与女性、MTF患者与男性之间的等位基因和基因分布差异均无统计学意义。这些发现可能提示其他未知基因可能参与了GIF的发生发展。因此，需要对GID进行全基因组关联研究或基因芯片分析，以确定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.