Hayes M Geoffrey, Urbanek Margrit, Ehrmann David A, Armstrong Loren L, Lee Ji Young, Sisk Ryan, Karaderi Tugce, Barber Thomas M, McCarthy Mark I, Franks Stephen, Lindgren Cecilia M, Welt Corrine K, Diamanti-Kandarakis Evanthia, Panidis Dimitrios, Goodarzi Mark O, Azziz Ricardo, Zhang Yi, James Roland G, Olivier Michael, Kissebah Ahmed H, Stener-Victorin Elisabet, Legro Richard S, Dunaif Andrea
1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [3] Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA.
1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Nat Commun. 2015 Aug 18;6:7502. doi: 10.1038/ncomms8502.
Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p23.1 [Corrected] and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.
多囊卵巢综合征(PCOS)是一种常见的、具有高度遗传性的复杂疾病,病因不明,其特征为雄激素过多、慢性无排卵以及葡萄糖稳态缺陷。相对于促卵泡激素分泌而言,黄体生成素增加、胰岛素抵抗以及发育期暴露于雄激素被认为在PCOS发病中起因果作用。在此,我们针对美国国立卫生研究院的PCOS表型(该表型具有发生代谢性疾病以及生殖激素水平异常的最高风险),在欧洲裔女性中绘制常见遗传易感性位点图谱。在病例对照荟萃分析中,三个位点达到全基因组显著性水平,两个新位点定位于8号染色体短臂23.1区[已修正]和11号染色体短臂14.1区,以及一个先前在中国PCOS患者中发现的9号染色体长臂22.32区的位点。位于促卵泡激素β多肽(FSHB)基因区域的同一个11号染色体短臂14.1单核苷酸多态性(SNP),即rs11031006,与PCOS诊断以及黄体生成素水平密切相关。这些发现提示神经内分泌变化在疾病发病机制中起作用。