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<p>Polycystic ovary syndrome (PCOS), the leading endocrine disorder in women of reproductive age, is highly heritable, yet its polygenic architecture remains poorly understood. Here we conducted a genome-wide association study on 12,419 Chinese women with PCOS and 34,235 controls, followed by a multi-ancestry meta-analysis with up to 13,773 European cases and 411,088 controls, identifying 94 independent loci, 73 of which were previously unreported. Despite different evolutionary pressures, Chinese and European ancestries showed substantial genetic overlap. Integrative functional analyses prioritized regulatory variants controlling gene activity in specific tissues, disease-causing genes including anti-Müllerian hormone (<i>AMH</i>), and biological pathways involving ligand-binding domain interactions and peroxisome proliferator-activated receptor gamma (PPARG) signaling. We identified granulosa cells as particularly important in PCOS development. Our genetics-driven drug discovery approach revealed multiple drug targets and repurposing opportunities, enabling personalized treatment strategies. These results enhance our understanding of the molecular basis of PCOS, paving the way for precision medicine.</p>

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Multi-ancestry genome-wide association analyses of polycystic ovary syndrome

  • 期刊论文

  • 发表日期：

    2025年11月4日

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  • Han Zhao,
  • Yuping Xu,
  • Baiqiang Xue,
  • Shigang Zhao,
  • Manfei Zhang,
  • Xiao-Ke Wu,
  • Tianjuan Wang,
  • Yanqin Wen,
  • Shumin Li,
  • Qing Zhang,
  • Ziyi Yang,
  • Hui Sun,
  • Ting Pan,
  • Yihong Lian,
  • Xueying Gao,
  • Chengwen Gao,
  • Zhao Wang,
  • Chuanhong Wu,
  • Changming Zhang,
  • Xuemin Jian,
  • Lixia Peng,
  • Xin Zhang,
  • Baokun Wang,
  • Lieqing Wei,
  • Yuyan He,
  • Disong Xia,
  • Ziyun Wu,
  • Qiangzhen Yang,
  • Yuanchao Sun,
  • Yonghe Ding,
  • Siyuan Du,
  • Guofeng Xia,
  • Yulong Jing,
  • Hairong Xu,
  • Weiye Shi,
  • Junting Liu,
  • Lin He,
  • Zi-Jiang Chen,
  • Yunxia Cao,
  • Zhiqiang Li,
  • Yongyong Shi

摘要

Polycystic ovary syndrome (PCOS), the leading endocrine disorder in women of reproductive age, is highly heritable, yet its polygenic architecture remains poorly understood. Here we conducted a genome-wide association study on 12,419 Chinese women with PCOS and 34,235 controls, followed by a multi-ancestry meta-analysis with up to 13,773 European cases and 411,088 controls, identifying 94 independent loci, 73 of which were previously unreported. Despite different evolutionary pressures, Chinese and European ancestries showed substantial genetic overlap. Integrative functional analyses prioritized regulatory variants controlling gene activity in specific tissues, disease-causing genes including anti-Müllerian hormone (AMH), and biological pathways involving ligand-binding domain interactions and peroxisome proliferator-activated receptor gamma (PPARG) signaling. We identified granulosa cells as particularly important in PCOS development. Our genetics-driven drug discovery approach revealed multiple drug targets and repurposing opportunities, enabling personalized treatment strategies. These results enhance our understanding of the molecular basis of PCOS, paving the way for precision medicine.