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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.

多囊卵巢综合征（PCOS）是一种高度遗传性、复杂的生殖和代谢疾病，影响全世界多达15%的育龄妇女。多囊卵巢综合征的病因尚不清楚，因此诊断标准，如NIH和Rotter-dam，是基于专家意见，而不是基于对疾病机制的了解。我们最近对欧洲（EA）祖先病例的全基因组关联研究（GWAS）的荟萃分析发现，遗传结构