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紊乱，约占绝经前妇女的7%。它在整个生命周期中具有主要的生殖和代谢发病率，包括肥胖、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T2D女性患有PCOS，使其成为最常见的T2D亚表型。多囊卵巢综合征的家族集群特征提供了遗传变异有助于其发病的证据。事实上，雄性和雌性一级亲缘都有生殖和代谢表型。此外，该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学中起直接作用。因此，尽管多囊卵巢综合征与肥胖和T2D有重叠，但其独特的表型特征提出了一个基本问题：多囊卵巢综合征是一种遗传上独特的疾病，还是相同的肥胖/T2D易感基因与其他遗传或环境因素相互作用导致多囊卵巢综合征的表型？我们已经在染色体19p13.2上的纤原蛋白3基因55内含子的二核苷酸重复（D19S884）中发现了一个与高雄激素血症相关的多囊卵巢综合征易感性等位基因。这种等位基因也与受影响女性及其兄弟的代谢表型有关。此前并没有发现纤颤蛋白-3是一种T2D易感基因，这表明PCOS的遗传分析可能会发现新的T2D基因。对于PCOS易感基因的定位，全基因组关联研究（GWAS）应该比连锁定位研究更有价值。我们组建了一个调查团队，他们在多囊卵巢综合征的表型分析和包括GWAS在内的复杂疾病的遗传分析方面拥有丰富的经验。我们有一个大队列广泛和一致表型的多囊卵巢综合征病例。我们将使用GWAS在约1200例PCOS病例和约3600例未选择的基于人群的女性对照中鉴定PCOS易感等位基因。这些对照队列具有诸如BMI等表型。有希望的变异将通过对约1800名PCOS病例和约5400名未选择女性对照的独立队列中1536个最有希望的snp的复制研究进一步研究。该项目不仅有望确定PCOS、高雄激素血症和不孕症的易感基因，还有望确定T2D、MBS和CVD的新风险位点。这些信息将导致更有效和更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.