Epigenetic heterogeneity in women with polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is a common endocrine disorder in women of reproductive age. As a clinically heterogeneous condition, distinct subtypes of PCOS may exist with varying clinical and biochemical features which impact clinical handling of PCOS. Identifying sub-clusters of PCOS women is a critical and challenging issue toward individualized treatment. Using data on the DNA methylome of PCOS cases and healthy controls, we performed an epigenome-wide association study (EWAS) on DNA methylation variability to investigate epigenetic heterogeneity of PCOS to explore the molecular basis in its clinical heterogeneity. We identified 136 CpG sites that are significantly highly variable in DNA methylation in PCOS cases (p < 1 × 10^-7). The EWAS results were significantly enriched for biological pathways including non-alcoholic fatty liver disease, polycomb repressive complex, and Hippo signaling pathway, all have been reportedly to involve in PCOS physiopathology. Based on the identified 136 significant sites, we were able to cluster PCOS cases into two major clusters. Correlation of the clusters with observed clinical variables found four reproductive hormones i.e. estradiol, progesterone, thyroid stimulating hormone and testosterone, that optimally characterize the clustering with high statistical significance (p = 1.50 × 10^-3). Our results showed that variability analysis of the PCOS DNA methylome can be a valuable approach for exploring the biological basis in PCOS clinical heterogeneity to promote individualized treatment and management.