Samant Medini, Bhat Mahalakshmi, Dadachanji Roshan, Sudhakar Digumarthi V S, Patil Anushree, Mukherjee Srabani
Department of Molecular Endocrinology, ICMR- National Institute for Research in Reproductive and Child Health, Parel, Mumbai, India.
Genetic Research Centre, ICMR- National Institute for Research in Reproductive and Child Health, Parel, Mumbai, India.
Syst Biol Reprod Med. 2025 Dec;71(1):76-89. doi: 10.1080/19396368.2025.2471418. Epub 2025 Mar 14.
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 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 (), rs143286842 (), and rs555458296 (). 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.
多囊卵巢综合征（PCOS）是一种复杂的多基因内分泌病，影响5%-20%的育龄妇女。家族研究、候选基因研究和全基因组关联研究（GWAS）已经确定了多个与PCOS相关的基因位点。本研究旨在确定与PCOS相关的功能性变异。我们应用全外显子组测序（WES）来确定85名特征明确的PCOS女性中的功能性变异。根据次要等位基因频率和致病性预测对注释的变异进行筛选。我们在研究组中发现201个基因中的234个罕见致病性非同义变异与PCOS有显著关联。这些基因与类固醇激素生物合成、卵巢类固醇生成、胰岛素抵抗和PI3K-Akt信号通路有关，这些通路在PCOS病理生理学中具有重要影响。此外，发现一些罕见变异在有胰岛素抵抗和无胰岛素抵抗的女性中是独特的，富集分析显示碳水化合物和脂质代谢在胰岛素抵抗的PCOS女性中尤其紊乱。通过Sanger测序验证了类固醇生成途径的变异，包括rs368902124（）、rs143286842（）和rs555458296（）。DUET分析表明这些变异破坏了其相应蛋白质的折叠。携带这些罕见变异的女性表现出激素谱改变以及高雄激素血症和高胰岛素血症的临床体征，强调了它们对PCOS病理生理学的影响。在本研究中已经揭示了几个功能性罕见变异与PCOS风险增加相关，从而扩展了印度女性对PCOS的遗传易感性范围。
