Genomic Basis of Premature Ovarian Insufficiency

描述(由申请人提供)：原始卵泡池衰竭是大多数女性原发性卵巢功能不全(POI)的原因。POI影响了1-4%的女性，而遗传因素对POI的影响高达70%。除了不孕不育，患有POI的妇女患骨质疏松症和心血管疾病的风险也增加了。目前，只有核型和FMR1预突变检测提供给POI女性。目前，对于有卵巢功能丧失风险的女性来说，保留生育能力是可行的，但缺乏能够预测卵巢功能不全的生物标志物。我们对识别与POI相关的遗传生物标记物感兴趣。我们之前已经使用动物模型来确定原始卵泡耗竭的调节因素和相关的遗传途径。处于生殖年龄的人的卵巢很难获得和研究，我们对卵泡池的耗竭和发生的了解大多来自动物模型。我们发现了一些新的基因，包括NOBOX、SOHLH1、SOHLH2、LHX8、Fig1a、FOXO3a和FOXL2，并利用转基因动物模型显示它们参与了原始卵泡的发生。我们之前在POI患者的一组女性中发现了NOBOX和Figla基因可能的突变，这表明在动物模型中发现的基因与人类卵巢发育和病理有关。使用现有动物模型的数据，我们确定目前有400多个基因与卵巢功能不全有关。这组基因我们称之为“卵巢体”。我们建议对家族性POI病例使用完整的外显子组测序，并以现有的1000个基因组数据库作为对照，以发现候选的病理变异。我们将在玛吉妇女医院招募的475例POI病例和1000名自然更年期对照中，使用前10个基因和最大的病理变异来复制它们的关联。我们还确保了具有500个POI病例和1000个对照的第二个复制队列的基因分型。我们将在511例POI病例和1000例自然绝经对照中应用SNP阵列技术，以确定某些基因组失衡是否与POI有关。我们假设，在超过10%的卵巢功能不全女性中，整个外显子组的病理性突变将会发生突变，并且这些突变中的相当大一部分将位于“卵巢体”基因集中。我们还假设，在超过10%的POI女性患者中，高分辨率阵列检测到的基因组失衡将优于传统的核型。我们的建议将为卵巢衰竭的风险评估定义新的遗传生物标记物，将有助于预测哪些女性可能受益于生育保护技术，并将通过发现与人类POI相关的新途径来刺激进一步的基础科学研究。

DESCRIPTION (provided by applicant): Primordial follicle pool depletion is the cause of primary ovarian insufficiency (POI) in most women. POI afflicts 1-4% of women, and genetics contributes as much as 70% to POI. Besides infertility, women with POI are at increased risk for osteoporosis and cardiovascular morbidity and mortality. Currently only karyotype and FMR1 pre-mutation testing are offered to women with POI. Fertility preservation is currently feasible fo women at risk for losing ovarian function, yet biomarkers capable of predicting ovarian insufficiency are lacking. We are interested in identifying genetic biomarkers that associate with POI. We have previously used animal models to identify regulators of primordial follicle depletion and associated genetic pathways. Human ovaries of reproductive age are difficult to access and study, and most of our understanding regarding follicular pool depletion and genesis derived from animal models. Others and we identified several novel genes including NOBOX, SOHLH1, SOHLH2, LHX8, FIGLA, FOXO3A, and FOXL2, and utilized transgenic animal models to show their involvement in primordial folliculogenesis. We previously identified plausible mutations in NOBOX and FIGLA genes in a subset of women with POI, which shows the relevance of genes discovered in animal models to human ovarian development and pathology. Using data from available animal models, we determined that there are currently over 400 genes implicated in ovarian insufficiency. This set of genes we call the "ovariome". We propose to use whole exome sequencing on familial POI cases and available 1,000 genomes database as a control, to discover candidate pathologic variants. We will use the top 10 genes and top pathologic variants to replicate their association in 475 POI cases and 1,000 natural menopause controls to be recruited here at Magee Women's Hospital. We have also secured to genotype a second replication cohort with 500 POI cases and 1,000 controls. We will apply SNP array technology on 511 POI cases and 1,000 natural menopause controls to determine if certain genomic imbalances associate with POI. We hypothesize that pathologic mutations in the whole exome will be mutated in greater than 10% of women with ovarian insufficiency, and that a substantial number of these mutations will be located in the "ovariome" set of genes. We also hypothesize that genomic imbalances detected by high-resolution arrays will be superior to conventional karyotype in identifying genomic imbalances in greater than 10% of women who suffer POI. Our proposal will define new genetic biomarkers for risk assessment of ovarian failure, will help predict women who may benefit from fertility preservation techniques, and will stimulate further basic science investigations by discovering novel pathways relevant to human POI.