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。1-4%的女性患有POI，而遗传因素对POI的影响高达70%。除不育外，POI妇女患骨质疏松症、心血管疾病和死亡率的风险增加。目前只有核型和FMR1突变前检测提供给POI妇女。对于有卵巢功能丧失风险的女性来说，保留生育能力目前是可行的，但目前缺乏能够预测卵巢功能不全的生物标志物。我们感兴趣的是识别与POI相关的遗传生物标志物。我们以前使用动物模型来确定原始卵泡耗竭的调节因子和相关的遗传途径。人类育龄卵巢难以接近和研究，我们对卵泡池衰竭和发生的了解大多来自动物模型。其他人和我们鉴定了几个新基因，包括NOBOX， SOHLH1, SOHLH2, LHX8， FIGLA， FOXO3A和FOXL2，并利用转基因动物模型显示它们参与原始卵泡发生。我们之前在POI女性亚群中发现了NOBOX和FIGLA基因的可能突变，这表明在动物模型中发现的基因与人类卵巢发育和病理相关。利用现有动物模型的数据，我们确定目前有超过400个基因与卵巢功能不全有关。这组基因我们称之为“卵巢”。我们建议使用家族性POI病例的全外显子组测序和现有的1000个基因组数据库作为对照，发现候选的病理变异。我们将使用最重要的10个基因和最重要的病理变异，在475例POI病例和1000例自然绝经对照中复制它们的关联，这些病例将在马吉妇女医院招募。我们还确保了第二个复制队列的基因分型，其中有500例POI病例和1000例对照。我们将对511例POI病例和1000例自然绝经对照者应用SNP阵列技术，以确定某些基因组失衡是否与POI相关。我们假设整个外显子组的病理突变将在超过10%的卵巢功能不全女性中发生突变，并且这些突变中有相当一部分将位于“卵巢”基因组中。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核型。我们的建议将为卵巢功能衰竭的风险评估定义新的遗传生物标志物，将有助于预测可能受益于生育能力保存技术的女性，并将通过发现与人类POI相关的新途径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.