Whole exome sequencing uncovers rare variants associated with PCOS susceptibility in Indian women

Polycystic ovary syndrome (PCOS) is a complex polygenic endocrinopathy affecting 5-20% of reproductive-age women. Familial studies, candidate gene studies, and GWAS have identified multiple PCOS-associated genetic loci. This study aims to identify the functional variants associated with PCOS. We applied whole exome sequencing (WES) to identify functional variants among eighty-five well-characterized women with PCOS. The annotated variants were filtered based on minor allele frequency and <i>in-silico</i> pathogenicity prediction. We found a significant association of 234 rare pathogenic nonsynonymous variants in 201 genes with PCOS in our study group. These genes are linked to steroid hormone biosynthesis, ovarian steroidogenesis, insulin resistance, and PI3K-Akt signaling pathway which are influential in PCOS pathophysiology. Further, several rare variants were found to be unique to women with and without insulin resistance, and enrichment analysis revealed that carbohydrate and lipid metabolism was especially deranged in insulin-resistant PCOS women. Variants of the steroidogenesis pathway were validated by Sanger sequencing including rs368902124 (<i>CYP19A1</i>), rs143286842 (<i>IGF1R</i>), and rs555458296 (<i>BMP-6</i>). <i>In-silico</i> analysis by DUET showed that these variants destabilized the folding of their corresponding protein. Women carrying these rare variants presented with altered hormonal profiles and clinical signs of hyperandrogenism and hyperinsulinemia, emphasizing their impact on PCOS pathophysiology. Several functional rare variants have been revealed to be associated with increased PCOS risk in the present study thus, expanding the genetic susceptibility landscape of Indian women to PCOS.