Louwers Yvonne V, Visser Jenny A, Dunaif Andrea, Laven Joop S E
Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Erasmus University Medical Center, Rotterdam, The Netherlands.
Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
Reproduction. 2025 Sep 26;170(5). doi: 10.1530/REP-25-0126. Print 2025 Nov 1.
Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder currently diagnosed only in reproductive-age women. Familial clustering and twin studies have provided strong evidence for a genetic contribution to PCOS pathogenesis. First-degree relatives, including males and non-reproductive-age females, have reproductive and metabolic phenotypes consistent with a genetic susceptibility to these traits. PCOS is now recognized as a complex trait influenced by both genetic and environmental factors. Genome-wide association studies have identified ∼30 loci linked to PCOS, implicating pathways involved in gonadotropin secretion and action, folliculogenesis, steroidogenesis, age at menopause, and carbohydrate metabolism. Next-generation sequencing has found rare variants in AMH, AMHR2, and DENND1A, supporting these genes' central role in developing PCOS. Epigenetic mechanisms, such as DNA methylation and non-coding RNAs, influence gene regulation and may contribute to phenotypic heterogeneity. Unsupervised clustering has identified distinct reproductive and metabolic subtypes with unique genetic architectures, providing a biologically meaningful framework for classification. This shift from expert opinion-based diagnosis to data-driven classification has the potential to transform PCOS management and enable precision medicine approaches tailored to distinct subtypes of the disorder.
多囊卵巢综合征（PCOS）是一种常见的异质性疾病，目前仅在育龄女性中被诊断出来。家族聚集性研究和双胞胎研究为PCOS发病机制中的遗传因素提供了有力证据。一级亲属，包括男性和非育龄女性，具有与这些特征的遗传易感性一致的生殖和代谢表型。PCOS现在被认为是一种受遗传和环境因素共同影响的复杂性状。全基因组关联研究已经确定了约30个与PCOS相关的基因座，涉及促性腺激素分泌和作用、卵泡生成、类固醇生成、绝经年龄以及碳水化合物代谢等途径。下一代测序在抗缪勒氏管激素（AMH）、抗缪勒氏管激素受体2（AMHR2）和含DENN结构域蛋白1A（DENND1A）中发现了罕见变异，支持这些基因在PCOS发生发展中的核心作用。表观遗传机制，如DNA甲基化和非编码RNA，影响基因调控，并可能导致表型异质性。无监督聚类已经识别出具有独特遗传结构的不同生殖和代谢亚型，为分类提供了一个具有生物学意义的框架。这种从基于专家意见的诊断向数据驱动分类的转变有可能改变PCOS的管理方式，并实现针对该疾病不同亚型的精准医学方法。
