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

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $664,113

## Abstract

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 investiga...

## Key facts

- **NIH application ID:** 10838466
- **Project number:** 5R01HD100812-05
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Andrea E Dunaif
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $664,113
- **Award type:** 5
- **Project period:** 2020-08-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838466

## Citation

> US National Institutes of Health, RePORTER application 10838466, Elucidating the Genetic Architecture of Metabolic and Reproductive PCOS Subtypes in Diverse Populations (5R01HD100812-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10838466. Licensed CC0.

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