CONTEXT Polycystic ovarian syndrome (PCOS) is a heterogeneous disorder, with disease loci identified from genome-wide association studies (GWAS) having largely unknown relationships to disease pathogenesis. OBJECTIVE To group PCOS GWAS loci into genetic clusters associated with disease pathophysiology. DESIGN/SETTING/PATIENTS OR OTHER PARTICIPANTS Cluster analysis was performed for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N=62,252). Associations with clinical outcomes (type 2 diabetes/T2D, coronary artery disease/CAD and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N=898,130, CARDIOGRAM/UKBB, N=547,261) and individual-level pPS in MGBB. INTERVENTIONS/MAIN OUTCOME MEASURES/RESULTS Four PCOS genetic clusters were identified with top loci indicated as following: (i) Cluster 1/Obesity/insulin resistance (FTO); (ii) Cluster 2/Hormonal/menstrual cycle changes (FSHB); (iii) Cluster 3/Blood markers/inflammation (ATXN2/SH2B3); (iv) Cluster 4/Metabolic changes (MAF, SLC38A11). Cluster pPS were associated with distinct clinical traits: Cluster 1 with increased body mass index (BMI; p=6.6x10-29); Cluster 2 with increased age of menarche (p= p=1.5x10-4); Cluster 3 with multiple decreased blood markers, including mean platelet volume (MPV; p=3.1 x10-5); and Cluster 4 with increased ALP (p=0.007). PCOS genetic clusters GWAS-pPS's were also associated with disease outcomes: Cluster 1 pPS with increased T2D (OR 1.07; p=7.3x10-50), with replication in MGBB all participants (OR 1.09, p=2.7x10-7) and females only (OR 1.11, 4.8x10-5). CONCLUSIONS Distinct genetic backgrounds in individuals with PCOS may underlie clinical heterogeneity and disease outcomes.

中文翻译：

---

遗传位点聚类涉及多囊卵巢综合征的生理途径。

背景 多囊卵巢综合征 (PCOS) 是一种异质性疾病，通过全基因组关联研究 (GWAS) 鉴定出的疾病位点与疾病发病机制的关系在很大程度上未知。目的 将 PCOS GWAS 基因座分组为与疾病病理生理学相关的遗传簇。设计/环境/患者或其他参与者 使用 GWAS 汇总统计数据对 60 个 PCOS 相关遗传变异和 49 个性状进行聚类分析。在 Mass General Brigham Biobank (MGBB, N=62,252) 中生成了簇特异性 PCOS 分区多基因评分 (pPS) 并测试其与临床表型的关联。使用基于 GWAS 的 pPS（DIAMANTE，N=898,130，CARDIOGRAM/UKBB，N=547,261）和个人水平 pPS 评估与临床结果（2 型糖尿病/T2D、冠状动脉疾病/CAD 和女性生殖特征）的关联。 MGBB。干预措施/主要结局指标/结果 确定了四个 PCOS 基因簇，其最高位点如下所示： (i) 簇 1/肥胖/胰岛素抵抗 (FTO)；(ii) 第 2 组/荷尔蒙/月经周期变化 (FSHB)；(iii) 簇 3/血液标志物/炎症 (ATXN2/SH2B3)；(iv) 簇 4/代谢变化（MAF、SLC38A11）。pPS 簇与不同的临床特征相关：簇 1 体重指数增加（BMI；p=6.6x10-29）；簇 1 体重指数增加（BMI；p=6.6x10-29）；簇 2 初潮年龄增加 (p= p=1.5x10-4)；集群 3 具有多项血液标志物下降，包括平均血小板体积 (MPV；p=3.1 x10-5)；集群 4 的 ALP 增加 (p=0.007)。PCOS 基因簇 GWAS-pPS 也与疾病结果相关：簇 1 pPS 伴有 T2D 增加（OR 1.07；p=7.3x10-50），在 MGBB 所有参与者（OR 1.09，p=2.7x10-7）和女性中复制仅（或 1.11、4.8x10-5）。结论 PCOS 患者的不同遗传背景可能是临床异质性和疾病结果的基础。