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

基本信息

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
项目类别：
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

项目摘要

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。全世界年龄女性的 PCOS 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，遗传结构由不同诊断标准定义的 PCOS 的总体相似性这一发现表明这些标准。相反，使用无监督的层次聚类分析无法识别生物学上不同的疾病亚型。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； “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) 相对较低我们在另一个 EA PCOS 队列中复制了这些亚型。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和一个与代谢亚型相关的基因座此外，这些基因座的效应大小相当大。比现有标准与 PCOS 诊断相关的 GWAS 位点更大。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 病例中我们的总体假设是，PCOS 存在多种表型亚型。我们将： (1) 检验额外 EA 中存在 PCOS 亚型的假设。我们将进行表型多样化的 PCOS 队列并评估这些亚型的遗传结构。额外 EA 中生殖和代谢数量性状的无监督层次聚类分析我们将正式评估遗传结构的差异并进行精细研究。映射 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。将按照目标 1 在 AA、HA 和 KA PCOS 病例对照队列中进行跨种族荟萃分析。 (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。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类卵泡膜、颗粒细胞和前脂肪细胞系中开发的报告基因检测将受到影响。使用基于 CRISPR/Cas9 的检测方法进行研究，这项研究将对人类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。