Epigenetic association analysis of clinical sub-phenotypes in patients with polycystic ovary syndrome (PCOS)

Abstract

Polycystic ovarian syndrome (PCOS) is a complex disorder affecting up to 15–20% of reproductive women. PCOS has recently been investigated using genome-wide association studies revealing important mutations and DNA methylation sites associated with the syndrome. As a clinically highly heterogenous condition, studying the molecular basis of the differential manifestation of PCOS is both meaningful concerning individualized management and important for understanding the biology of PCOS. Using genome-wide DNA methylation data collected from PCOS patients, we performed a powerful region-based analysis to detect differentially methylated regions (DMR) by correlating DNA methylation pattern in a genomic region with the level of each PCOS clinical sub-phenotype. We identified seven significant DMRs on chromosome 19 (12877188-12876846 bp) and chromosome 6 (MHC region) associated with prolactin level, as well as chromosomes 11 and 2 associated with metabolic attributes. Functional annotation linked significant DNA methylation patterns to functional genes (HOOK2, BDNFl, HLA-G, HLA-H, HLA-J, RNF39, etc) of metabolic disorders and immunity or novel associations to serve as targets for validation and replication.

摘要

多囊卵巢综合征(PCOS)是一种复杂的疾病, 影响多达15-20%的育龄期妇女。最近通过全基因组关联研究揭示了与PCOS相关的重要突变和DNA甲基化位点。作为一种临床高度异质性的疾病, 研究多囊卵巢综合征差异表现的分子学基础, 对于个体化管理具有重要意义, 而且对PCOS特征的了解意义重大。利用从PCOS患者收集的全基因组DNA甲基化数据, 评估基因组的差异甲基化区域(DMR)甲基化情况与PCOS临床亚表型的相关性。我们在19号染色体(12877188-12876846bp)、6号染色体(MHC区), 以及与代谢属性相关的11号和2号染色体上发现了7个与泌乳素水平显著相关的DMRs。功能注释将重要的DNA甲基化情况与代谢紊乱、免疫或新关联的功能基因 (HOOK2、BDNFl、HLA-G、HLA-H、HLA-J、RNF39等) 联系起来, 是验证和复制的目标。

The Chinese abstracts are translated by Prof. Dr. Xiangyan Ruan and her team: Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China.

Keywords:

• PCOS
• clinical heterogeneity
• DNA methylation
• differentially methylated regions

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was jointly supported by the Region of Southern Denmark 2012 research grant project no. 12/6629, the Novo Nordisk Foundation Medical and Natural Sciences Research Grant NNF13OC0007493 and by the Shandong Provincial Natural Science Foundation in China (grant no. ZR2014HP026).