Table 3.

List of the top five Identified signalling pathways with CpG-associated genes from our EWAS analysis.

	IP A Pathway	Genes from our dataset	PCOS associated pathology or gene	References
# 1	Molecular mechanisms of cancer	BMPR1A, CASP9, GNA11, LRP1, PRKCA, SHH and SUFU	A well-recognised PCOS associated pathology is endometrial cancer	Shen et al. (2013)
#2	Cardiogenesis	BMPR1A, LRP1 and PRKCA	BMPR1A is PCOS related and LRP1 is involved in lipid metabolism. Also, PCOS is frequently accompanied by an increased risk for cardiovascular disease, because of molecular interactions between obesity, testosterone and dyslipidemia Couto Alves et al., 2017
#3	Sonic Hedgehog (SH) signalling	SHH and SUFU	SH is involved in ovarian follicular growth, regulating the steroidogenic capacity of endocrine cells like GLCs and signalling oocyte maturation, especially towards the final stages of antral follicle development. One of the key features of PCOS is the production of multiple prematurely arrested follicles leading to reduced fertility. Therefore, it is plausible that SH may be implicated in the development of anovulation in PCOS	Wijgerde et al., 2005; Spicer et al., 2009 Wang et al., 2014
#4	Nur77, T-lymphocytes signalling	CASP9 and CD86	Nur77 is related to autoimmune response prevention. PCOS development and progression have been associated with immune response. It has been hypothesized that functional autoantibodies lead to a higher prevalence of autoimmune thyroiditis amongst PCOS patients. Also, several studies have indicated a link between increased androgen levels in PCOS patients, and inflammatory conditions, both systemic and GLC localised	Gleicher et al., 2007 Adams et al., 2016 Xu et al., 2016
#5	Mitochondrial dysfunction	CASP9, COX15 and TRAK1	Mitochondrial biogenesis is particularly important during oocyte growth and its impairment has been associated with poor oocyte quality, diminished ovarian reserves and insulin resistance. Although patients selected for the study did not suffer from insulin resistance or hyperinsulinemia, these findings suggest a potential predisposition to insulin signalling disruption that may prove functionally significant given that methylation changes can precede clinical manifestation of the disease by several years	Wang et al., 2014 Wang and Moley, 2010 Brower et al., 2015 Ding et al., 2017 Moran et al., 2016