Epigenetic and Expression Analysis of PCOS

多囊卵巢综合征(PCOS)是一种由睾酮水平升高定义的复杂表型 和闭经/月经过少。它发生在约7%的育龄妇女中，而且 与肥胖、胰岛素抵抗和患2型糖尿病(T2D)风险增加相关。 虽然多囊卵巢综合征有很强的家族成分，并已被证明具有高度的遗传性(H2=0.8)，但传统的 我们实验室和其他实验室进行的遗传学研究只确定了有限数量的可复制的 多囊卵巢综合征易感基因座。从目前对多囊卵巢综合征和其他复杂基因的遗传学研究中可以清楚地看出 常见遗传变异的表型不能解释观察到的大部分遗传力。一 对这种观察到的缺陷的可能解释是，在复杂表型中观察到的遗传力是由于 表观遗传而不是基因组变异。表观遗传变化是指基因表达或基因表达的可遗传变化 在DNA序列没有变化的情况下出现的细胞表型。DNA甲基化的变异 模式是表观遗传变异的一种主要形式，可以通过甲基化在基因组水平上捕捉到 测试&gt；450,000个DNA甲基化位点的特定DNA阵列。我们假设：1)一个重要的 多囊卵巢综合征遗传性的组成部分是由于表观遗传变化，包括乙基化模式的变化， 2)这些甲基化模式的变化与表达模式的变化相关，以及3)这些 甲基化的变化要么是由于DNA的特定变化，要么是由于环境因素，包括 在宫内环境中。我们建议通过评估差异DNA甲基化来检验这些假说 肥胖女性靶组织(肌肉、内脏脂肪、皮下脂肪和肝脏)的状况 差异甲基化对基因表达的影响，以及差异甲基化是否 状态取决于基因组或表观遗传事件。多囊卵巢综合征是严重影响人类健康的常见综合征。 受影响妇女及其一级亲属的健康，每年捐款超过40亿美元 我们的医疗保健成本。拟议的研究将增加我们对潜在途径的了解 在多囊卵巢综合征中受到影响，并有可能改进对这种普遍综合征的治疗。 相关性(见说明)； 多囊卵巢综合征是一种常见的疾病，由男性性激素兴奋和月经不调定义，强烈 与肥胖和糖尿病有关。目前的遗传方法未能识别出大部分的 导致多囊卵巢综合征易感性的遗传因素。我们建议评估表观遗传变异的作用， 在多囊卵巢综合征的病因中，在没有DNA变化的情况下发生的基因表达的可遗传变化

Polycystic Ovary Syndrome (PCOS) is a complex phenotype that is defined by elevated testosterone levels and amenorrhea/oligomenorrhea. It occurs in ~7% of reproductive age women and is also strongly associated with obesity, insulin resistance, and an increased risk of developing Type 2 Diabetes (T2D). While PCOS has a strong familial component and has been shown to be highly heritable (h2=0.8), traditional genetic studies conducted by our laboratory and others have identified only a limited number of reproducible PCOS susceptibility genetic loci. It is clear from current genetic studies of PCOS and other complex genetic phenotypes that common genetic variation does not explain the bulk of the observed heritability. One possible explanation for this observed deficit is that the observed heritability in complex phenotypes is due to epigenetic rather than genomic variation. Epigenetic changes are heritable changes in gene expression or cellular phenotype that occur in the absence of changes to the DNA sequence. Variation in DNA methylation patterns is one major form of epigenetic variation and can be captured on a genomic level using methylation specific DNA arrays that test >450,000 DNA methylation sites. We hypothesize that: 1) a significant component of the heritability of PCOS is due to epigenetic changes including variation in niethylation pattern, 2) these changes in methylation patterns correlate with changes in expression patterns, and 3) these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment. We propose to test these hypotheses by assessing the differential DNA methylation status in target tissues (muscle, visceral fat, subcutaneous fat, and liver) of obese women with and without PCOS, the impact of differential methylation on gene expression, and whether the differential methylation status is due to genomic or epigenetic event. PCOS is common syndrome which severely impacts the health of affected women and their first degree relatives and contributes greater than $4 billion annually to our health care costs. The proposed studies will increase our understanding to the underlying pathways that are affected in PCOS and with the potential of improved treatment for this pervasive syndrome. RELEVANCE (See instructions); PCOS is a common disorder defined by elvated male sex hormones and irregular menses and is strongly associated with obesity and diabetes. Current genetic approaches have failed to identify the bulk of the hertitable factors contributing to PCOS susceptibility. We propose to asses the role of epigenetic variation, heritable changes in gene expression that occur in the absence of DNA changes, in the cause of PCOS