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，影响多达15％的生殖 - 全球年龄妇女。 PCOS的病因仍然未知，因此诊断标准，例如NIH和鹿特 - 大坝是基于专家意见而不是基于疾病机制的知识。我们最近的荟萃分析 欧洲（EA）祖先案例的全基因组协会研究（GWAS）发现遗传结构 由不同的诊断标准定义的PCOS通常相似。这一发现表明这些标准 请勿识别生物学上不同的疾病亚型。相反，使用无监督的分层群集分析 在EA PCOS中，我们确定了两个PCOS亚型：一个“生殖”组，其特征是较高的黄体素化。 货币（LH）和性激素结合球蛋白（SHBG）水平相对较低和胰岛素水平；和 具有较高BMI以及葡萄糖和胰岛素水平的“代谢”组，相对低SHBG 和LH水平。我们在附加的EA PCOS队列中复制了这些亚型。我们与 亚型，发现了六个新型基因座在全基因组的意义上，五个基因座与复制性亚型相关 和一个与代谢亚型相关的基因座。此外，这些基因座的效果大小基本上是 大于与PCOS诊断相关的GWAS基因座通过现有标准相关的。我们有令人兴奋的前 这些亚型存在于非裔美国人（AA），西班牙裔（HA）和East的PCOS病例中 亚洲（韩国，KA）血统。我们的总体假设是，PCOS有表型亚型 独特的遗传结构。我们将：（1）检验以下假设：其他EA中有PCOS的亚型 同性pcos的人群并评估这些亚型的遗传结构。我们将表演 额外的EA-An-生殖和代谢定量性状的无监督分层群集分析 Cestry PCOS病例对照人群。我们将正式评估遗传结构的差异，并进行精细的 映射GWAS数据以选择AIM 3功能研究的变体。 （2）测试亚型是 出现在非洲，西班牙裔和东亚血统和评估这些遗传建筑中 亚型。聚类分析，具有亚型的GWA，遗传结构的评估和精细映射将是 在AA，HA和KA PCOS病例对照组中的AIM 1中进行。跨种族的荟萃分析将进行 导管以利用基因发现的祖先差异。 （3）检验高优先级变体的假设 与PCOS亚型相关的与疾病发病机理有关的组织起作用。我们将确定 来自目标1和2的非编码遗传变异，导致具有高通量的遗传关联信号 我们在人类theca，颗粒和脂肪细胞前细胞系中开发的记者断言。受影响的基因将 可以使用基于CRISPR/CAS9的测定法进行研究。这项研究将对 通过定义PCOS的生物学相关亚型并在关键途径中识别因果变异的领域 与潜水员种群中的PCOS发病机理有关。