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，约占该人群的7%。它在整个生命周期中具有主要的生殖和代谢疾病，包括肥胖症、2型糖尿病（T2 D）、代谢综合征（MBS）和其他心血管疾病（CVD）风险因素的患病率显著增加。据估计，约25%的绝经前T2 D女性患有PCOS，这可能是最常见的T2 D亚表型。多囊卵巢综合征的家族聚集性特征为遗传变异参与其发病机制提供了证据。事实上，男性和女性一级亲属都有生殖和代谢表型。此外，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PCOS与肥胖和T2 D重叠，但其独特的表型特征提出了一个根本问题：PCOS是一种遗传上不同的疾病，还是相同的肥胖/T2 D易感基因与其他遗传或环境因素相互作用导致PCOS表型？我们已经在染色体19p13.2上的Escherin-3基因内含子55的二核苷酸重复序列（D19 S884）中鉴定出一个PCOS易感等位基因，该等位基因与高雄激素血症相关。该等位基因也与受影响的女性及其兄弟的代谢表型相关。原纤维蛋白-3以前没有被认为是T2 D易感基因，这表明PCOS的遗传分析可能会发现新的T2 D基因。全基因组关联研究（GWAS）应提供更多的权力比连锁定位PCOS易感基因的研究。我们已经组建了一个调查小组，在PCOS的表型和包括GWAS在内的复杂疾病的遗传分析方面拥有丰富的经验。我们有一个大的队列广泛和一致的表型PCOS病例。我们将使用GWAS在约1，200例PCOS病例和约3，600例基于人群的女性对照中确定PCOS易感性等位基因。这些对照队列具有可用的表型，例如BMI。有希望的变异将进一步研究使用1536个最有希望的SNPs的复制研究在一个独立的队列约1,800例PCOS病例和约5,400例女性对照。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T2 D，MBS和CVD的新风险位点。这些信息应该导致更有效和具体的治疗以及疾病的预测和预防。

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.