FRI457 Protein-coding Genetic Variation In Polycystic Ovary Syndrome
Authors: Parker Chloe , Bauer Rosemary , Welt Corrine Kolka , Legro Richard S , Geoffrey Hayes M , Urbanek Margrit 
Published: October 2023

Disclosure: C. Parker: None. R. Bauer: None. C.K. Welt: None. R.S. Legro: None. M.G. Hayes: None. M. Urbanek: None.

Background: Polycystic ovary syndrome (PCOS) is a multisystem endocrine disorder and is the most common form of anovulatory infertility of reproductive aged women (6-15%). PCOS is characterized by the presence of hyperandrogenemia, irregular menses, and polycystic ovarian morphology. A previous twin study has shown PCOS to be highly heritable (h2=0.72). Thus, we hypothesize that genetic variation is a major contributor to the etiology of PCOS. Objective: Our goal is to identify the genetic factors that contribute to the PCOS phenotype and how they define phenotypic subtypes of PCOS with the aim of better understanding PCOS pathology and optimizing treatment strategies for individual women. Methodology: We are performing whole exome sequencing (WES) supplemented with genomic regions mapping to PCOS GWAS loci on 772 subjects with PCOS and 300 age and ancestry-matched controls to generate a comprehensive catalog of PCOS-associated protein coding variants. We will use prediction tools to identify likely-to-be deleterious variants and in silico evidence of epigenetic modification to identify PCOS associated genes/pathways. We will then prioritize variants for molecular follow-up creating a comprehensive catalog of protein coding variants associated with PCOS. We expect the variants identified by WES to map to multiple genes and pathways including novel genes/pathways which have not previously been implicated in PCOS as well as genes/pathways that have previously been shown or predicted to play a major role in the etiology of PCOS by us or other groups. Results: To date we have obtained high quality sequencing data on 772 women with PCOS. Sequencing of 300 age and ancestry matched reproductively heathy women is being started. We have identified 81 rare protein coding genetic variants using targeted re-sequencing in three distinct pathways in an independent PCOS cohort. These genes are associated with insulin resistance, the gonadotropin signaling pathway and the Anti-Müllerian Hormone (AMH) signaling pathway. We identified 37 functionally validated deleterious variants in genes that encode AMH or its cognate receptor AMHR2, 7 rare variants that encode LMNA, 11 rare (MAF &lt;0.1) variants that encode the insulin receptor, and 26 coding variants for the genes encoding the beta subunit of gonadotropins, LH and FSH, and their receptors, FSHR and LHCGR. Conclusion: We have identified 81 rare protein altering genetic variants in pathways that are predicted to be impaired in individuals with PCOS supporting a critical role for genetics in the etiology of PCOS. Our WES screen will allow us to generate a comprehensive catalog of likely to be deleterious PCOS associated variants. This catalog of variants will identify the genes/pathways that are mutated in PCOS leading to improved personalized phenotyping and treatment of PCOS.

Presentation Date: Friday, June 16, 2023