Genome-Wide Association Scan of Polycystic Ovary Syndrome Phenotypes

多囊卵巢综合征表型的全基因组关联扫描

• 批准号: 7581936
• 负责人: Andrea E Dunaif
• 金额: $ 239.32万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7581936
• 关键词: 19p13.2; Affect; Alleles; Brothers; Cardiovascular Diseases; Chromosome Mapping; Chromosomes; Complex; Custom; Dinucleotide Repeats; Disease; Endocrine System Diseases; Environmental Risk Factor; Etiology; European; Family; Female; First Degree Relative; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Healthcare Systems; Hereditary Disease; Infertility; Introns; Lead; Link; Longevity; Metabolic; Metabolic syndrome; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Phase; Phenotype; Play; Polycystic Ovary Syndrome; Population; Predisposition; Premenopause; Prevalence; Prevention; Risk; Risk Factors; Role; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Susceptibility Gene; Syndrome; Technology; Variant; Woman; cardiovascular disorder risk; cohort; cost; experience; fibrillin; genetic analysis; genome wide association study; improved; male; novel; population based; reproductive; 19p13.2; Affect; Alleles; Brothers; Cardiovascular Diseases; Chromosome Mapping; Chromosomes; Complex; Custom; Dinucleotide Repeats; Disease; Endocrine System Diseases; Environmental Risk Factor; Etiology; European; Family; Female; First Degree Relative; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Healthcare Systems; Hereditary Disease; Infertility; Introns; Lead; Link; Longevity; Metabolic; Metabolic syndrome; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Phase; Phenotype; Play; Polycystic Ovary Syndrome; Population; Predisposition; Premenopause; Prevalence; Prevention; Risk; Risk Factors; Role; Sampling; Signal Transduction; Single Nucleotide Polymorphism; Susceptibility Gene; Syndrome; Technology; Variant; Woman; cardiovascular disorder risk; cohort; cost; experience; fibrillin; genetic analysis; genome wide association study; improved; male; novel; population based; reproductive

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.

多囊卵巢综合征（PCOS）是绝经前妇女最常见的内分泌疾病，影响了约7％的人群。它在整个生命周期中具有主要的生殖和代谢性病，包括肥胖症的患病率显着提高，2型糖尿病（T2D），代谢综合征（MBS）和其他心血管疾病（CVD）风险因素。据估计，约有25％的T2D的绝经前女性患有PCOS，这可能是最常见的T2D亚表现型。家族中PCOS群集的特征提供了证据表明遗传变异有助于其发病机理。实际上，男性和女性一级亲属具有生殖和代谢表型。此外，综合征的基本生殖特征，高雄激素血症似乎在相关代谢异常的病因中起着直接的作用。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是遗传上不同的疾病还是相同的肥胖/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？我们已经确定了在19p13.2染色体19p13.2上的内含子55中的二核苷酸重复（D19S884）中的一个PCOS敏感性等位基因，该基因与高雄激素血症有关。该等位基因还与受影响妇女及其兄弟的代谢表型有关。原纤维素-3以前没有被视为T2D易感基因，表明PCOS的遗传分析可能鉴定出新型T2D基因。全基因组关联研究（GWAS）应提供的功率比链接映射研究用于定位PCOS易感基因。我们组建了一个调查团队，该团队在表型PCOS以及包括GWAS在内的复杂疾病的遗传分析方面具有丰富的经验。我们有大量的广泛，一致的表型PCOS病例。我们将采用GWAS在约1,200例PCOS病例中识别PCOS易感性等位基因和〜3,600个未选择的基于人群的女性对照。这些控制队列具有表型，例如可用的BMI。在〜1,800个PCOS病例和约5,400个未选择的女性对照组中，使用1536个最有希望的SNP的复制研究将进一步研究有希望的变体。该项目有望不仅鉴定PCOS，高雄激素血症和不育症的敏感性基因，而且还可以确定T2D，MBS和CVD的新风险基因座。这些信息应导致更有效，更具体的治疗以及疾病预测和预防。