16- Genome-Wide Studies in Polycystic Ovary Syndrome and multiancestry analyses: a systematic review with equity in mind

Polycystic Ovary Syndrome (PCOS) is a complex polygenic disorder that manifests as a reproductive/fertility disorder with symptoms such as irregular menstrual cycles, hyperandrogenemia, polycystic ovaries, hirsutism, insulin resistance, and other cardiometabolic sequelae. Genome-wide Association Studies computing polygenic risk scores and Gene-by-Environment studies have sought to discover novel loci associated with PCOS (such as, DENND1A, THADA, FSHR, ERBB4) that are involved in glucose regulation, follicle growth, and oncogenesis. Most of these studies use biobanks that primarily include or are restricted to non-Hispanic European ancestry populations for discovery. Such underutilization of diverse samples might impact the effective clinical implementation of the results to diverse samples. PCOS still largely remains a disorder that disproportionately affects minority populations such as Hispanic/Latinas in the US, yet exclusion of non-European ancestry populations persists due to statistical confounding arising from risk allele effect heterogeneity and due to preferences for consistent and significant genetic findings. Here we report a systematic review of 29 studies drawn from the literature (22 from GWAS catalog and 9 from PubMed searches) showing the strong and validated genetic loci and their putative causal link to PCOS etiology. Given the imperative underscored by the 2023 NASEM report on use of population descriptors in genetics/omics research, we provide an analysis of selection biases and descriptor inconsistencies for Hispanic/Latinas across databases to improve equity in future PCOS research and care, and we outline accountability for reasonableness-based criteria and make recommendations for leveraging multiancestry data to improve discovery in future studies and translation to diverse populations.