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：
10632022
负责人：
Andrea E Dunaif
金额：
$ 67.52万
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/10632022
关键词：
Adipocytes Affect African African American Age Asian ancestry Biological Assay Body mass index CRISPR/Cas technology Cell Line Cluster Analysis Cohort Studies Complex Data Diagnosis Disease East Asian Etiology European European ancestry Expert Opinion Genes Genetic Diseases Glucose Heritability Hispanic Human Infertility Insulin Knowledge Koreans Luteinizing Hormone Maps Meta-Analysis Metabolic Metabolic Diseases Neurosecretory Systems Non-Insulin-Dependent Diabetes Mellitus Obesity Pathogenesis Pathway interactions Patient Self-Report Phenotype Polycystic Ovary Syndrome Population Population Heterogeneity Regulator Genes Reporter Research Series Sex Hormone-Binding Globulin Signal Transduction Testing Tissues United States National Institutes of Health Untranslated RNA Variant Woman anovulatory infertility case control case finding causal variant cohort diagnostic criteria 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 timeline trait young woman

项目摘要

PCOS (polycystic ovary syndrome) 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（多囊卵巢综合征）是一种高度可遗传的，复杂的生殖和代谢疾病，影响了全球多达15％的生殖时代女性。 PCOS的病因仍然未知，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知识的。我们最近对欧洲（EA）血统案例的全基因组关联研究（GWAS）的荟萃分析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，我们确定了两种PCOS亚型：一个“生殖”组，其特征是较高的叶酸马匹（LH）和性马匹结合球蛋白（SHBG）水平，其BMI和胰岛素水平相对较低；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数据，这些亚型存在于非裔美国人（AA），西班牙裔（HA）和East的PCOS案例中亚洲（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。我们将表演其他EA-Cestry PCOS病例对照组中生殖和代谢定量性状的无监督分层聚类分析。我们将正式评估遗传结构的差异，并对GWAS数据进行精细映射以选择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被策划，以利用祖先的基因发现差异。（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。