Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome
Family-Based Quantitative Trait Meta-Analysis Implicates Rare Noncoding Variants in DENND1A in Polycystic Ovary Syndrome
复制标题
DOI：
10.1210/jc.2018-02496
复制
发表时间：
2019-09-01
影响因子：
5.8
通讯作者：
Hayes, M. Geoffrey
中科院分区：
文献类型：
--
作者：
Dapas, Matthew;Sisk, Ryan;Hayes, M. Geoffrey
内容：多囊卵巢综合征（PCOS）是绝经前妇女最常见的内分泌疾病之一，根据所应用的诊断标准，影响5%至15%的这一人群。其特征是高雄激素血症、排卵功能障碍和多囊卵巢形态。PCOS是高度遗传性的，但只有一小部分这种遗传性可以占到由常见的遗传易感性的变种确定到data.Objective：本研究的目的是测试是否罕见的遗传变异有助于PCOS pathogenetics.Design，患者和方法：我们进行了全基因组测序的DNA从261个人62个家庭与一个或多个女儿与PCOS。我们使用数量性状荟萃分析检测了罕见变异与PCOS及其伴随的激素性状的关联。（P = 5.31 x 10（-5），校正后P = 0.039）与PCOS家族的生殖和代谢特征显著相关。DENND 1A的常见变异先前在全基因组关联研究中与PCOS诊断相关。随后的研究表明，DEND 1A是人类卵巢雄激素生物合成的重要调节因子。我们的研究结果提供了额外的证据表明DEND 1A在PCOS中起着核心作用，并表明罕见的非编码变体有助于疾病的发病机制。
Context: Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5% to 15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.Objective: The objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and Methods: We performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis.Results: We found rare variants in DENND1A (P = 5.31 x 10(-5), adjusted P = 0.039) that were significantly associated with reproductive and metabolic traits in PCOS families.Conclusions: Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.