Genome-Wide Association Scan of Polycystic Ovary Syndrome Phenotypes

多囊卵巢综合征(PCOS)是绝经前妇女最常见的内分泌疾病，约占绝经前妇女的7%。它在一生中有主要的生殖和代谢疾病，包括肥胖症、2型糖尿病(T2D)、代谢综合征(MBS)和其他心血管疾病(CVD)危险因素的患病率显著增加。据估计，约25%的绝经前妇女患有多囊卵巢综合征，这可能是最常见的T2D亚型。多囊卵巢综合征的家系聚集性特征为其发病机制提供了遗传变异的证据。事实上，男性和女性一级亲属都有生殖和代谢表型。此外，综合征的主要生殖特征，高雄激素血症，似乎在相关代谢异常的病因中发挥了直接作用。因此，尽管PCOS与肥胖和T2D重叠，但其独特的表型特征提出了一个基本问题：PCOS是一种遗传上截然不同的疾病，还是同样的肥胖/T2D易感基因与导致PCOS表型的其他遗传或环境因素相互作用？我们已经在染色体19p13.2上纤维蛋白-3基因内含子55的二核苷酸重复序列(D19S884)中发现了一个PCOS易感等位基因，该等位基因与高雄激素血症有关。该等位基因还与受影响的妇女及其兄弟的代谢表型有关。纤维蛋白-3以前没有被认为是T2D易感基因，这表明PCOS的遗传分析可能识别新的T2D基因。全基因组关联研究在定位PCOS易感基因方面应该比连锁作图研究提供更多的力量。我们组建了一支在多囊卵巢综合征表型和复杂疾病的遗传分析方面拥有丰富经验的研究团队，包括Gwas。我们有大量广泛且一致的多囊卵巢综合征病例。我们将使用GWAS在大约1,200例PCOS病例和~3,600例未选择的基于人群的女性对照中识别PCOS易感等位基因。这些对照队列具有BMI等表型。将通过对1536个最有希望的SNPs的复制研究，在约1800例多囊卵巢综合征患者和约5400名未经选择的女性对照的独立队列中进一步研究有希望的变异。该项目不仅有望识别多囊卵巢综合征、高雄激素血症和不孕症的易感基因，而且还有望识别T2D、MBS和CVD的新危险基因。这些信息应导致更有效和具体的治疗以及疾病预测和预防。

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of premenopausal women, affecting ~7% of this population. It has major reproductive and metabolic morbidities across the lifespan, including markedly increased prevalence rates of obesity, type 2 diabetes (T2D), metabolic syndrome (MBS) and other cardiovascular disease (CVD) risk factors. It has been estimated that ~25% of premenopausal women with T2D have PCOS, making it perhaps the most common T2D subphenotype. The features of PCOS cluster within families providing evidence that genetic variation contributes to their pathogenesis. Indeed, male as well as female first-degree relatives have reproductive and metabolic phenotypes. Further, the cardinal reproductive feature of the syndrome, hyperandrogenemia, appears to play a direct role in the etiology of the associated metabolic abnormalities. Thus, although PCOS overlaps with obesity and T2D, its unique phenotypic features raise the fundamental question: Is PCOS a genetically distinct disorder or do the same obesity/T2D susceptibility genes interact with additional genetic or environmental factors resulting in the PCOS phenotype? We have already identified one PCOS susceptibility allele within a dinucleotide repeat (D19S884) in intron 55 of the fibrillin-3 gene on chromosome 19p13.2 that is linked and associated with hyperandrogenemia. This allele is also associated with metabolic phenotypes in affected women and their brothers. Fibrillin-3 has not been previously implicated as a T2D susceptibility gene suggesting that genetic analyses of PCOS may identify novel T2D genes. Genome-wide association studies (GWAS) should provide more power than linkage mapping studies for localizing PCOS susceptibility genes. We have assembled an investigative team that has extensive experience in phenotyping PCOS and in the genetic analysis of complex diseases including GWAS. We have a large cohort of extensively and consistently phenotyped PCOS cases. We will employ GWAS to identify PCOS susceptibility alleles in ~1,200 PCOS cases and ~3,600 unselected population-based female controls. These control cohorts have phenotypes such as BMI available. Promising variants will be further investigated using replication studies of the 1536 most promising SNPs in an independent cohort of ~1,800 PCOS cases and ~5,400 unselected female controls. This project promises to identify not only susceptibility genes for PCOS, hyperandrogenemia and infertility but also novel risk loci for T2D, MBS and CVD. This information should lead to more effective and specific treatments as well as to disease prediction and prevention.