Genetics and Epigenetics of Polycystic Ovary Syndrome

Abstract

Polycystic ovary syndrome (PCOS) is one of the most common endocrinological and reproductive disorders in women of reproductive age with a global prevalence rate of 5–20%. It is a clinically and genetically heterogeneous disorder. There have been multiple reports from independent research groups from different ethnicities that a variety of factors, including genetics and epigenetics, significantly contribute to the etiopathogenesis of PCOS. GWAS, twin studies, and genotype-phenotype association studies have resulted in the identification of more than a dozen candidate genes/loci with PCOS. In the proposed book chapter, we aim to provide insight and discuss the role of various genetic and epigenetic elements that are responsible for PCOS globally and in India. This book chapter should serve as a reference to all the basic researchers and healthcare professionals on the genetics and epigenetics of PCOS.

1. Introduction

Stein and Leventhal were the first to describe women with amenorrhea, hirsutism, obesity, and ovaries that appeared to be polycystic in seven independent cases [1] and termed it as Stein-Leventhal syndrome which was subsequently referred to as polycystic ovary syndrome (PCOS). PCOS is a complex reproductive and endocrinological disorder in women of the reproductive age group across the globe. PCOS is characterized by the presence of hyperandrogenism (HA), ovulatory dysfunction (OD), and/or the presence of unilateral or bilateral polycystic ovarian morphology (PCOM).

PCOS is a multifactorial disorder with complex aetiopathophysiology. Several factors including genetic, epigenetic, lifestyle, nutrition, ethnicity, and environment are known to contribute to PCOS [2]. However, the quantum of each factor contributing to the overall phenotype is not yet ascertained. PCOS is one of the major causes of anovulatory infertility and these patients are predicted to have a high risk of developing endometrial cancer [3].

2. Clinical signs and symptoms

The three main clinical signs and symptoms of PCOS include hyperandrogenism (clinical/biochemical), menstrual irregularities (oligomenorrhoea, amenorrhoea, and/or followed by prolonged or heavy periods), and polycystic ovarian morphology (PCOM) [4].

Firstly, clinical hyperandrogenism presents itself as acne, hirsutism, alopecia, and acanthosis nigricans, and biological hyperandrogenism as excess of androgen production. Secondly, hormonal imbalance such as elevated levels of luteinizing hormone, disrupted ratio of luteinizing hormone to follicle-stimulating hormone (LH: FSH), increased Amh (anti-mullerian hormone) levels, etc. results in the development of cysts in the ovary and leads to irregular menstruation that includes anovulation and amenorrhea/oligomenorrhea [4], further leading to PCOS. Lastly, the PCOM refers to the presence of 12 or more follicles in the ovary with a diameter of 2–9 mm and an ovarian volume of around 10 ml or greater [5, 6, 7].

Various cardio-metabolic disorders are also associated with PCOS that include hyperlipidemia, insulin resistance, hypertension, type 2 diabetes mellitus, cardiovascular disease, etc. [8]. PCOS patients have also been reported to have increased neonatal complications such as pre-eclampsia, preterm birth, gestational diabetes, early pregnancy loss, etc. [9].

3. Prevalence

The global prevalence rate of PCOS was reported to be between 5 and 20% of women of reproductive age [10]. A study by Liu and co-workers analyzed the burden of PCOS to be approximately one and a half million globally, after analyzing the data in women of reproductive age ranging between 15 and 49 years across 194 counties [11]. The World Health Organization (2021) reported that approximately 116 million women (3.4%) suffer from PCOS globally [12]. Few independent research groups have reported different symptoms and prevalence rates of PCOS among different ethnicities [13, 14]. The wide difference in the prevalence rates across the globe is due to multiple reasons that include the different criteria being followed for diagnosis, ethnicity, time of publication, survey populations, etc. [15, 16, 17, 18, 19, 20].

The prevalence rate of PCOS in India is reported to be ranging between 3.7% and 22.5% among women of the reproductive age group [19, 20]. A systematic review and meta-analysis by Bharali et al. reported the pooled prevalence of PCOS in Indian women to be 5.8% as per the NIH criteria and 10% as per the Rotterdam’s criteria and AES criteria respectively [21].

4. Diagnosis and grading of the severity of PCOS

The definition and the diagnostic criteria for PCOS were initially laid down by The National Institute for Child Health and Human Development (NICHD), USA conference in the year 1990. As per this conference, diagnostic characteristics for PCOS included clinical and/or biochemical hyperandrogenism and menstrual irregularities [22]. The American Society for Reproductive Medicine (ASRM), European Society of Human Reproduction and Embryology (ESHRE) presented the Rotterdam criteria in 2003. According to this, at least two out of three criteria are mandatory (oligo-ovulation or anovulation, clinical or biochemical hyperandrogenism, and/or the presence of polycystic ovarian morphology), for a patient to be diagnosed with PCOS [23]. The Androgen Excess and PCOS Society, considered PCOS as primarily a hyperandrogenic disorder and defined PCOS as the presence of clinical and/or biochemical hyperandrogenism accompanied by either oligo-ovulation or polycystic ovarian morphology [24].

Rotterdam criteria is one of the widely accepted criteria for diagnosing PCOS. As per this classification, PCOS patients have been sub-grouped into four different phenotypes, namely, phenotype A (Frank or Classic polycystic type) with HA + OD + PCOM, phenotype B (Classic non-cystic type) with HA + OD, phenotype C (Non classic ovulatory type) with HA + PCOM, and phenotype D (Non classic mild or normo-androgenic type) with OD + PCOM symptoms [25].

5. Genetics of PCOS

The role of genetics in PCOS was first proposed by Cooper et al. on chromosomal analysis of 18 families of American origin and had reported an autosomal dominant mode of inheritance and decreased penetrance [26]. Wilroy and coworkers [27] observed that the male relatives of PCOS patients were diagnosed with oligospermia and increased LH secretion, suggesting an X-linked mode of inheritance. The same study also reported the association of PCOS with metabolic co-morbidities like diabetes mellitus, dyslipidaemia, hypertension, and arteriosclerosis [27]. An increase in the incidence of infertility, oligomenorrhea, and hirsutism in first-degree relatives of PCOS patients and an increased degree of baldness in male relatives was reported by Ferriman and Purdie [28]. Twin studies have suggested PCOS to be a polygenic disorder influenced by both intrauterine and extrauterine environmental factors [29, 30].

6. Few candidate genes associated with PCOS

To date, independent studies from different ethnicities and research groups have reported more than a dozen candidate genes/loci for PCOS. Majority of these candidate genes have been broadly classified into the six major pathways/groups. A few important genes in each category/pathway have been mentioned below:

1. Ovarian and adrenal steroidogenesis pathway (CYP11A, CYP17, CYP19)

2. Gonadotropin action and regulation pathway (LHCGR, AMH, FSHR)

3. Steroid hormone effects pathway (AR, SHBG)

4. Insulin action and secretion pathway (INS, INSR, CAPN10)

5. Chronic inflammation pathway (TNFA)

6. Energy homeostasis pathway (leptin and receptor genes, ADIPOQ , and PPARG)

6.1 CYP11A (cytochrome P450 family 11 subfamily A) gene

The locus for the CYP11A gene (Ensembl ID: ENSG00000140459) is 15q24.1. The CYP11A gene is approximately 20 kb in size and has 9 exons. CYP11A gene codes for a total of nine mRNA transcripts out of which only six codes for the functional protein. The largest transcript (ENST00000268053.11) is 1837 bp and encodes for the cholesterol side-chain cleavage enzyme (cytochrome P450scc) with 521 amino acids and an approximate molecular weight of 60 kDa.

The cholesterol side-chain cleavage enzyme (cytochrome P450scc) initiates steroidogenesis and converts cholesterol to pregnenolone. Cyp11a is expressed in the adrenal cortex, ovaries, testis, and placenta in humans [31]. Pathogenic mutations in the CYP11A gene have been reported in multiple diseases such as P450scc insufficiency, XY sex reversal and adrenal insufficiency, Adrenal hyperplasia, Adrenal hypospadias, etc. [31].

Gharani et al. [32] and Diamanti-Kandarakis and co-workers [33] reported a significant correlation between the alleles of the CYP11A gene with a 5′ untranslated region (UTR) consisting of repeats of a (tttta)n pentanucleotide and serum testosterone levels in PCOS patients. Wang et al. reported that the allele of (tttta)n microsatellite polymorphism in the promoter of the CYP11A gene has a higher frequency and is associated with increased BMI in the Chinese population with PCOS [34]. Zhang and co-workers reported that the SNP rs4077582 in CYP11A1 is positively correlated to PCOS susceptibility and affects testosterone levels by regulating LH [35].

Pusalkar and coworkers found that variations in the promoter region of CYP11A1 and CYP17 were associated with testosterone levels in PCOS patients in the Indian population [36]. Further, this polymorphism was suggested as a potential molecular marker for PCOS by Reddy et al. in the South Indian population [37]. On the contrary, Gaasenbeek et al. studied the polymorphisms of the CYP11A promoter region in PCOS patients from the United Kingdom and Finland and found no significant correlation [38].

6.2 CYP17 (cytochrome P450 family 17) gene

The locus for the human CYP17 gene (Ensembl ID: ENSG00000148795) is 10q24.32. This gene codes for a total of 8 mRNA transcripts out of which five codes for a functional protein. The largest transcript (ENST00000369887.4) is 1750 bp and encodes for cytochrome P450 17α-hydroxylase protein with 508 amino acids and an approximate molecular weight of 57.4 kDa. Cytochrome P450 17α-hydroxylase enzyme is primarily located in the endoplasmic reticulum in humans and has hydroxylase and lyase activity. It converts progesterone and pregnenolone into 17-hydroxyprogesterone and 17-hydroxypregnenolone respectively and subsequently to 4-androstenedione and dehydroepiandrosterone [39].

Escobar-Morreale et al. reported an increased P450c17α activity in PCOS women with hyperandrogenism in the adrenal cortex and ovaries [40]. Two independent reports by Wickenheisser and co-workers have concluded that there is higher transactivation of CYP17 promoter in ovarian theca cells and dysregulation in the expression of CYP17 at the mRNA level [41, 42]. A T/C SNP in the promoter region was found to be associated with PCOS in the Caucasian and Greek populations by Carey et al. [43] and Diamanti-Kandarakis et al. [44] respectively. The CYP17 gene is primarily responsible for the development of insulin resistance and a hyperandrogenic phenotype in PCOS patients [45, 46].

Kaur et al. reported a − 34 T > C polymorphism in CYP17A1 that was found to be associated with PCOS in the north Indian population [47]. Few studies have reported a negative correlation between CYP17 polymorphisms and PCOS [48, 49, 50, 51].

Besides PCOS, mutations in the CYP17 gene have also been reported in 17-alpha-hydroxylase/17, 20-lyase deficiency, Steroid-17 alpha-hydroxylase deficiency, Pseudohermaphroditism, etc. [31].

6.3 CYP19 (cytochrome P450 family 19) gene

The locus for the CYP19 gene (Ensembl ID: ENSG00000137869) is 15q21. The size of this gene is approximately 70 kb and has 10 exons. CYP19 gene codes for 19 transcripts, out of which only 12 codes for a functional protein. The largest transcript (ENST00000396402.6) codes for Aromatase (P450arom) or estrogen synthetase enzyme, which is 4403 bp and with 503 amino acids and has a molecular weight of approximately 53 kDa. The estrogen synthetase enzyme catalyzes the tranformation of the C19 testosterone androstenedione, and androgens, to the C18 estradiol, estrone and estrogens, respectively [46]. In humans, the expression of P450arom is in the bone, adipose stromal cells, ovary, placenta, and few foetal tissues [52].

Petry et al. [53] and Medeiros et al. [54] identified a deficiency of aromatase activity in patients with PCOS and hyperandrogenism in the British and Brazilian populations respectively [53, 54]. Yu et al. reported reduced CYP19A1 expression in ovaries due to hypermethylation of its promoter region in PCOS patients from China [55]. Chen et al. reported a significant decrease in the activity of P450arom in both lean and obese women with PCOS [56]. In a multicentric study, the SNP (rs2414096) was reported to have a positive association between reduced aromatase activity, increased estradiol to testosterone ratio (E2/T), and PCOS development in Caucasian and African patients [57]. These findings were further corroborated by independent research groups in the Chinese [58] and Iranian [59] populations. Few studies have reported that a tetranucleotide repeat (TTTA)n in the CYP19 gene with short alleles results in the inhibition of the aromatase activity and hyperandrogenism along with a high LH: FSH ratio [60, 61].

Ashraf et al. reported a SNP (rs2414096) of the CYP19 gene to be associated the PCOS susceptibility and hyperandrogenism in patients from Kashmir, India [62].

6.4 LHCGR (luteinizing hormone/choriogonadotropin receptor) gene

The locus for the LHCGR gene (ENSG00000138039) is on chromosome 2p16.3 and has a size of approximately 80kbp. This gene codes for a total of six mRNA transcripts, out of which only five code for the functional protein, luteinizing hormone (LH)/ choriogonadotropin receptor. The largest transcript (ENST00000294954.12) is 3076 bp with 699 amino acids with an approximate molecular weight of 33 kDa.

The LHCGR gene, which is crucial for ovulation in response to the mid-cycle LH surge, is mostly expressed in the granulosa cells of preovulatory follicles in females [63]. The luteinizing hormone is a member of the G protein-coupled receptors (GPCR) subfamily N and is characterized by the presence of a large N-terminal extracellular domain with leucine-rich repeats (LRR).

Elevated LH levels are a common characteristic in PCOS patients, and are related to anovulation, as luteinizing hormone has a negative effect on the development of eggs [64]. Furui et al. reported two missense pathogenic mutations (Trp8Arg and Ilg15Thr) in the gene coding for the beta-subunit of the luteinizing hormone in PCOS patients [65]. On the contrary, a multinational and multicentric study by Nilsson et al. reported these changes in the normal population also [66]. Takahashi and co-workers reported many SNPs in the promoter site of the LH gene that were common to patients with PCOS and other ovulatory disorders [67]. GWAS studies have identified the 2p16.3 region containing LHCGR loci to be associated with PCOS in Han Chinese [68] and European populations [69]. An SNP (rs2293275) that induces an amino acid substitution (S312N) was reported in the Sardinian population with PCOS [70].

Thathapudi and co-workers reported the SNP (rs2293275) in the LHCGR gene to be associated with PCOS from Southern India [71]. Singh et al. suggested that a mutant allele (C) of rs12470652 and mutant genotype (AA) and mutant allele (A) of rs2293275 conferred a high risk of PCOS progression in the North Indian population [72].

Genetic analysis of 150 PCOS families of European and Caribbean origin for pathogenic mutations, in a total of 37 potential candidate genes, resulted in no significant correlation between the LH gene and PCOS [73].

6.5 FSHR (follicle-stimulating hormone receptor) gene

The locus for the FSHR gene (ENSG00000170820) is 2p21 and it is approximately 54 kbp in size. This gene codes for a total of five mRNA transcripts, out of which only three code for the functional protein- follicle-stimulating hormone (FSH). The largest transcript (ENST00000406846.7) is 2762 bp with 695 amino acids with an approximate molecular weight of 30 kDa. FSH promotes oogenesis, follicle development, and gametogenesis, which results in follicular maturation and granulosa cell proliferation [74].

Mutations in FSHR gene have been associated with ovarian hyperstimulation syndrome, ovarian cancer, premature ovarian insufficiency with resistant ovary syndrome, etc. Hypogonadotropic hypogonadism is caused by an inactivating mutation in the FSHR gene, which also causes arrests of the preantral stage of follicle development [75].

GWAS study in Han Chinese population by Shi et al. reported the association of the FSHR gene with PCOS [76]. Two SNPs, Thr307Ala and Asn680Ser in exon 10 of the FSHR gene have been found to be associated with PCOS from Italian [77] and South Korean populations [78]. While the SNP (rs2268361) was reported to be associated with PCOS in the Chinese population [79] it was not in the Dutch population [80].

6.6 AMH (anti-Mullerian hormone) gene

The locus for the AMH gene (ENSG00000104899) is 19p13.3. AMH gene codes for a total of three transcripts out of which only one transcript (ENST00000221496.5) encodes the functional protein-Anti-mullerian hormone (AMH). The size of the gene is 2.8 kbp with 5 exons. The AMH protein is a homo-dimeric precursor protein and has a molecular weight of approximately 140 kDa. The two-polypeptide chains contain a large N-terminal prodomain and a small C-terminal mature domain. The Sertoli and granulosa cells contain the major transcription initiation site, located 10 bp upstream of the ATG codon.

Amh protein has been found to suppress the release of estradiol (E2) and limit the development of ovarian follicles in response to serum FSH in the cells [81]. It regulates the early change from primordial follicles that are at rest, to developing follicles in females. Studies have reported that AMH^−/+gene null mice recruit more primordial follicles as compared to wild-type mice but also show an early depletion of their primordial follicles stock [82]. The primary pathophysiologic circumstance for the start of PCOS is follicular arrest, which is caused by Amh’s interference with follicular development and recruitment. Amh also suppresses FSH-induced aromatase activity, which promotes the development of other PCOS-related clinical symptoms such as excess androgen and insulin resistance [83].

Zheng et al. reported that AMH gene polymorphism (rs10407022) is linked to insulin resistance in PCOS patients from China [84]. An unbiased WGS analysis of 80 PCOS patients by Gorsic et al. resulted in identifying a total of 24 rare variants in patients of European ancestry [85].

Kevenaar and co-workers reported that genetic variants in the AMH and AMHR2 genes did not influence PCOS susceptibility in Dutch Caucasian patients, however, they found that AMH Ile⁴⁹Ser polymorphism had a positive correlation with follicle number and androgen levels [86].

6.7 AR (androgen receptor) gene

The locus for the AR gene (ENSG00000169083) is Xq12 and it has a size of 90 kbp. This gene has a total of eight transcripts out of which only three codes for the protein-androgen receptor protein.

The AR protein has three major domains, the N-terminal domain, the DNA-binding domain, and the androgen-binding domain. It belongs to a family of nuclear transcription factors. In humans, AR is present in theca interna cells and granulosa cells of preantral follicles, antral follicles, and dominant follicles. The first exon of the AR gene embeds a VNTR polymorphism consisting of CAG repeats those codes for a polyglutamine chain in the N-terminal transactivation domain.

A study by Hickey et al. reported a significantly higher frequency of alleles with longer CAG repeats (>22 repeats) in PCOS patients with infertility compared to fertile Caucasian women from Australian [87]. However, Mifsud et al. found no significant differences between the anovulatory PCOS patients and controls in the distribution of the CAG repeats [88]. Xia et al. reported that shorter alleles of the (CAG)n in the first exon of AR gene enhanced the PCOS susceptibility either by upregulating AR activity or resulting in hyperandrogenism in the PCOS patients from China [89] and these findings were also corroborated in the Caucasian population [90]. Rajender et al. reported that CAG bi-allelic mean length and allele distribution did not differ between controls and cases in PCOS cases from India [91].

At least two separate studies from the Chinese population have reported an association between higher serum testosterone levels in PCOS with CAG repeat length [92, 93]. Peng and coworkers reported that the SNP (rs6152G/A) leads to significantly higher susceptibility to polycystic ovary syndrome in Chinese patients [94]. Yuan et al. reported a positive correlation between GGN repeat polymorphism in the AR gene and PCOS in the Han Chinese population [95].

6.8 SHBG (sex hormone binding globulin) gene

The locus of the SHBG gene (ENSG00000129214) is 17p13. This gene codes for a total of 21 mRNA transcripts out of which only seventeen codes for the functional protein-sex hormone-binding globulin or sex steroid-binding globulin protein. The largest transcript (ENST00000380450.9) is 1267 bp long and has 402 amino acids with an approximate molecular weight of 90 kDa.

SHBG controls the level of sex hormones by binding to androgens, mainly with testosterone and estrogens. It is primarily synthesized by hepatocytes and controlled by multiple metabolic factors, such as androgens and insulin. The SHBG receptors are expressed in human sex-steroid-dependent cells and a wide range of tissues that include hypothalamus, colon, ovaries, prostate, etc. [96]. Concentrations of SHBG are lower in females with PCOS, due to the inhibitory effect of hyperinsulinemia on SHBG synthesis [97]. Low serum SHBG levels in PCOS women also result in hyperandrogenic symptoms such as hirsutism, acne, androgenic alopecia, and virilization [98, 99].

Hogeveen et al. reported two novel mutations, firstly, Pro156Leu, associated with abnormal glycosylation and low SHBG secretion, and a frameshift mutation in exon 8 (E326) which resulted in truncated SHBG synthesis, in a PCOS patient from France [100]. Xita et al. reported that longer allele genotypes showed a positive association with lower SHBG levels in PCOS women from Greece [101]. The same group had further reported that the combination of long SHBG alleles with short CYP19 alleles results in increased testosterone levels, elevated levels of Free androgen index (FAI), Dehydroepiandrosterone-sulphate hormone (DHEAS), T/E2 ratios and low SHBG levels [102]. An independent study on PCOS women from Bahrain by Abu-Hijleh and co-workers reported that specific SHBG variants and haplotypes spanning six polymorphisms were linked to increased or decreased PCOS susceptibility [103].

6.9 INS (insulin) gene

The locus for the INS gene (ENSG00000254647) is 11p15.5. This gene codes for a total of 5 transcripts out of which only four codes for a functional protein. The largest transcript (ENST00000381330.5) is 465 bp long with 110 amino acids and codes for the Insulin protein. It has a variable tandem repeat (VNTR) embedded at its 5′ regulatory region ranging between 26 and 200 in number. The VNTR polymorphism in the INS gene has three size classes. Class-I, II and III comprises of an average length of 40, 80 and an average of 157 repeats respectively [9].

Waterworth et al. [104] reported an association of PCOS with allelic variations in the INS VNTR locus. They had observed that the class III alleles were associated with anovulatory PCOS in populations from the UK. The transmission of these allelic variations was more commonly from fathers than from mothers to affected daughters. The same study also observed that the geometric mean of fasting serum insulin concentrations was significantly higher in families with evidence of linkage [104]. Michelmore et al. demonstrated that women with polycystic ovarian morphology had increased insulin sensitivity and leptin resistance, related to insulin gene VNTR class III alleles [105].

Multiple independent studies of INS VNTR polymorphisms with PCOS found no signification association in Spanish [106], Czech women [107], United Kingdom, and Finland populations [108].

6.10 INSR (insulin receptor) gene

The locus for the INSR gene (ENSG00000171105) is 19p13.2. This gene has 7 available transcripts out of which only three code for the protein, insulin receptor. The largest transcript (ENST00000302850.10) is 9463 bp long with 1382 amino acids. It is a hetero-tetrameric glycoprotein composed of two α and two β-subunits and plays a significant role in insulin metabolism. The significance of the insulin signaling in PCOS is substantiated by the HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans) [109]. Insulin resistance results in pituitary LH hypersecretion, increased testosterone production in theca cells, increased P450scc activity in granulosa cells, and disruption of follicular maturation, all of which contribute to PCOS susceptibility [110].

Two independent research groups have reported that the C/T SNP at His1058 in the seventeen exon of the INSR gene is associated with PCOS in the Caucasian and Chinese populations [111, 112]. Jin et al. reported a novel T/C polymorphism at Cys1008 resulting in decreased insulin sensitivity in Chinese PCOS women [113]. A microsatellite marker D19S884, located on chromosome 19p13.2, close to the INSR gene has been reported to be associated with PCOS in the Caucasian [114] and European population [115].

Mukherjee et al. found a significant association of C/T polymorphism at His1058 of the INSR gene in lean PCOS women while not in obese PCOS patients from Maharashtra, India [116].

6.11 PPARG (peroxisome proliferator-activated receptor-gamma) gene

The locus for the PPARG gene (ENSG00000132170) is 3p25.2. The size of the gene is approximately 100 kb with 9 exons. PPARG gene has a total of 34 transcripts and only twenty-two codes for the functional protein, peroxisome proliferator-activated receptor-γ. PPARG is primarily found in adipose tissue and large intestine and intermediate levels are found in the kidney, liver, and small intestine in humans and is involved in energy metabolism and adipogenesis pathway. Mutations in this gene have been linked to Partial lipodystrophy, type 2 diabetes, and dyslipidemia [117].

Hahn et al. [118] and Shaikh et al. [119] reported that a Pro12Ala polymorphism (rs1801282) of the PPARG gene in PCOS women is associated with lower hirsutism scores and increased insulin sensitivity in German and Indian population respectively. Studies by Korhonen et al. [120] and Yilmaz et al. [121] have also reported the role of this SNP in the pathogenesis of PCOS and supported its role as a protective factor against the development of diabetes mellitus in first-degree relatives of PCOS patients. Zhang et al. performed a metanalysis and reported the rs1801282 C > G polymorphism to be a protective factor in PCOS susceptibility [122].

7. Epigenetics of PCOS

The term “epigenetics” is used to describe variations that are not encoded by changes in DNA sequence and refer to several cellular elements and processes that are involved in the regulation of transcription that includes DNA modifications, non-coding RNAs, chromatin structure, and nuclear architecture. The epigenetic changes are usually transient and are heritable in daughter cells post division [123].

Wang et al. [124] reported 7929 differentially methylated CpG sites and 650 differential transcripts by combining DNA methylation profile and transcriptome analysis, in the ovaries of PCOS patients of Chinese origin. In the same study, they identified 54 genes with methylated levels correlating with gene transcription in PCOS. They also found increased hypomethylated sites and less hypermethylated sites, residing in CpG islands and N_Shore in PCOS [124]. Yu et al. [125] observed that the level of methylation was significantly higher in CpG island shores and lower within the gene bodies in Chinese cohort of PCOS patients. This study also reported that high CpG content promoters were frequently hypermethylated in PCOS ovaries but were hypomethylated in case controls [125]. Jones and coworkers identified increased methylation in the INSR locus and reduced methylation in the LHCGR locus in PCOS patients from the USA [126]. Kokosar et al. identified 440 sites with differential CpG methylation in the adipose tissue of PCOS patients [127]. Xu and coworkers [128] reported that DNA methylation altered the PCOS granulosa cells while hydroxymethylation did not have any significant effect. They identified 6936 differentially methylated CpG sites between the control and PCOS-obesity patients and 12,245 differentially methylated CpG sites were identified between the control and PCOS-nonobesity group [128]. Nillson et al. [129] found 85 differentially expressed transcripts in the skeletal muscles of PCOS patients but only two CpG sites exhibited differential DNA methylation after multiple testing. In the same study, they also reported that PCOS has epigenetic and transcriptional changes in skeletal muscle that can explain the metabolic abnormalities seen in these patients [129]. Sagvekar et al. reported that intrinsic changes in the transcriptional control of TETs and DNMT3A may contribute to DNA methylation modifications in CGCs of PCOS women in India [130].

8. Conclusion

PCOS is a serious multifactorial disorder of women in the reproductive age group resulting primarily in infertility and other gynecological issues. The etiopathology of PCOS is poorly understood. This disease presents itself differently in different ethnic groups, with few characteristics showing more in one population, and other sets of characteristics in another. While different medical organizations/associations have proposed the diagnostic criteria for PCOS based on the different clinical signs and symptoms, there is still a gray area; none of these classifications consider any molecular genetics aspects.

The role of genetic and epigenetic factors in PCOS has been widely substantiated by extensive research findings from different parts of the world in the literature. In the current book chapter, we have provided insight into the genetic and epigenetic factors that are associated with PCOS.

The results of the molecular studies along with the clinical data/ current diagnostic parameters might help in the identification of novel molecular markers to detect all PCOS phenotypes, grading the severity and in better understanding of the etiopathology of PCOS patients and thereby aiding in better clinical management.

Acknowledgments

Ms. Adity Paul acknowledges the financial support received in the form of a fellowship from Tezpur University.

Conflict of interest

The authors declare no conflict of interest.