Elucidating the Genetic Architecture of Metabolic and Reproductive PCOS Subtypes in Diverse Populations

阐明不同人群代谢和生殖 PCOS 亚型的遗传结构

• 批准号: 10223397
• 负责人: Andrea E Dunaif
• 金额: $ 66.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10223397
• 关键词: Affect; African; African American; Age; Asians; Biological; Biological Assay; Body mass index; CRISPR/Cas technology; Cell Line; Cluster Analysis; Cohort Studies; Complex; Data; Diagnosis; Diagnostic; Disease; Duct (organ) structure; Etiology; European; Expert Opinion; Genes; Genetic; Genetic Diseases; Glucose; Heritability; Hispanics; Human; Infertility; Insulin; Knowledge; Koreans; Luteinizing Hormone; Meta-Analysis; Metabolic; Metabolic Diseases; Neurosecretory Systems; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathway interactions; Patient Self-Report; Phenotype; Population; Population Heterogeneity; Regulator Genes; Reporter; Research; Series; Sex Hormone-Binding Globulin; Signal Transduction; Testing; TimeLine; Tissues; United States National Institutes of Health; Untranslated RNA; Variant; Woman; base; case control; causal variant; cohort; disorder subtype; functional genomics; gene discovery; genetic architecture; genetic association; genetic variant; genome wide association study; genome-wide; high body mass index; individualized medicine; insight; novel; reproductive; reproductive system disorder; trait; young woman

PCOS is a highly heritable, complex reproductive and metabolic disorder affecting up to 15% of reproductive- age women worldwide. The etiology of PCOS remains unknown so the diagnostic criteria, e.g. NIH and Rotter- dam, are based on expert opinion rather than on knowledge of disease mechanisms. Our recent meta-analysis of genomewide association studies (GWAS) of European (EA) ancestry cases found that the genetic architecture of PCOS defined by the different diagnostic criteria was generally similar. This finding suggests that these criteria do not identify biologically distinct disease subtypes. In contrast, using unsupervised hierarchical cluster analysis in EA PCOS, we identified two PCOS subtypes: a “reproductive” group characterized by higher luteinizing hor- mone (LH) and sex hormone binding globulin (SHBG) levels with relatively low BMI and insulin levels; and a “metabolic” group characterized by higher BMI as well as glucose and insulin levels with relatively low SHBG and LH levels. We replicated these subtypes in an additional EA PCOS cohort. We performed GWAS with the subtypes and found six novel loci at genomewide significance, five loci associated with the reproductive subtype and one locus associated with the metabolic subtype. Further, the effect sizes for these loci were substantially greater than those GWAS loci associated with PCOS diagnosis by the existing criteria. We have exciting pre- liminary data that these subtypes are present in PCOS cases of African American (AA), Hispanic (HA) and East Asian (Korean, KA) ancestry. Our overarching hypothesis is that there are phenotypic subtypes of PCOS with distinct genetic architecture. We will: (1) Test the hypothesis that there are subtypes of PCOS in additional EA cohorts of phenotypically diverse PCOS and assess the genetic architecture of these subtypes. We will perform unsupervised hierarchical cluster analysis of reproductive and metabolic quantitative traits in additional EA an- cestry PCOS case-control cohorts. We will formally assess differences in genetic architecture and conduct fine- mapping of GWAS data to select variants for Aim 3 functional studies. (2) Test the hypothesis that subtypes are present in PCOS of African, Hispanic and East Asian ancestry and assess the genetic architecture of these subtypes. Cluster analysis, GWAS with subtypes, assessment of genetic architecture and fine-mapping will be performed as in Aim 1 in AA, HA and KA PCOS case-control cohorts. Transethnic meta-analysis will be con- ducted to leverage differences in ancestry for gene discovery. (3) Test the hypothesis that high priority variants associated with PCOS subtypes are functional in tissues relevant to disease pathogenesis. We will identify the noncoding genetic variants from Aims 1 and 2 causing the genetic association signals with a high-throughput reporter assay we developed in human theca, granulosa and preadipocyte cell lines. The genes impacted will be investigated using CRISPR/Cas9-based assays. This research will have a sustained and lasting impact on the field by defining biologically relevant subtypes of PCOS and identifying causal variants in key pathways related to PCOS pathogenesis in diverse populations.

PCOS 是一种高度遗传、复杂的生殖和代谢疾病，影响高达 15% 的生殖系统疾病。 全世界适龄妇女。 PCOS 的病因仍不清楚，因此诊断标准，例如NIH 和 Rotter- dam，是基于专家意见而不是疾病机制的知识。我们最近的荟萃分析 对欧洲 (EA) 血统病例的全基因组关联研究 (GWAS) 发现，遗传结构 不同诊断标准定义的PCOS总体相似。这一发现表明这些标准 不能识别生物学上不同的疾病亚型。相反，使用无监督层次聚类分析 在 EA PCOS 中，我们确定了两种 PCOS 亚型：“生殖”组，其特征是黄体生成激素较高。 激素 (LH) 和性激素结合球蛋白 (SHBG) 水平，BMI 和胰岛素水平相对较低；和一个 “代谢”组的特点是较高的 BMI 以及较高的葡萄糖和胰岛素水平，而性激素结合球蛋白 (SHBG) 相对较低 和 LH 水平。我们在另一个 EA PCOS 队列中复制了这些亚型。我们进行了 GWAS 亚型，发现了六个具有全基因组意义的新基因座，五个与生殖亚型相关的基因座 以及一个与代谢亚型相关的基因座。此外，这些位点的效应大小基本上是 大于根据现有标准与 PCOS 诊断相关的 GWAS 位点。我们有激动人心的预 初步数据表明，这些亚型存在于非裔美国人 (AA)、西班牙裔 (HA) 和东方人的 PCOS 病例中 亚洲（韩国，KA）血统。我们的首要假设是，PCOS 存在以下表型亚型： 独特的遗传结构。我们将： (1) 检验额外 EA 中存在 PCOS 亚型的假设 表型多样化的 PCOS 队列并评估这些亚型的遗传结构。我们将表演 额外 EA 中生殖和代谢数量性状的无监督层次聚类分析 cestry PCOS 病例对照队列。我们将正式评估遗传结构的差异并进行精细的研究 绘制 GWAS 数据以选择 Aim 3 功能研究的变体。 (2) 检验亚型是的假设 存在于非洲、西班牙和东亚血统的多囊卵巢综合症中，并评估这些人的遗传结构 亚型。聚类分析、亚型 GWAS、遗传结构评估和精细绘图将 在 AA、HA 和 KA PCOS 病例对照队列中按照目标 1 进行操作。跨种族荟萃分析将是 旨在利用血统差异进行基因发现。 (3) 检验高优先级变体的假设 与 PCOS 亚型相关的基因在与疾病发病机制相关的组织中具有功能。我们将确定 来自目标 1 和 2 的非编码遗传变异导致高通量的遗传关联信号 我们在人卵泡膜、颗粒细胞和前脂肪细胞系中开发了报告基因测定法。受影响的基因将 使用基于 CRISPR/Cas9 的检测进行研究。这项研究将对以下领域产生持续和持久的影响： 通过定义 PCOS 的生物学相关亚型并识别关键途径中的因果变异来推动该领域的发展 与不同人群中 PCOS 的发病机制有关。