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Deciphering the DNA Methylome of Polycystic Ovary Syndrome

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Abstract

Polycystic ovary syndrome (PCOS) is a hormonal disorder common among women of reproductive age. PCOS is characterized by ovarian dysfunction and metabolic abnormalities with widely varying clinical manifestations brought about by intricate mechanisms of interplay between the genome and the environment. The popularity of epigenome-wide association studies (EWASs) is helping to facilitate the discovery of environment-mediated molecular modification in PCOS from disease etiology to epigenetic marker discovery. Current epigenetic studies have provided convincing observational evidence linking epigenetic regulation with PCOS origin, manifestation, clinical heterogeneity and comorbidity, which could lead to improved management of the disease through efficient intervention and prevention strategies. Several biological pathways have been consistently reported by independent studies, revealing functional regulation due to endocrine abnormalities and metabolic dysfunction in PCOS, while also suggesting an autoimmune component in the condition. The use of high-throughput sequencing technologies for analysing the epigenome integrated with causal inferences is expected to facilitate effective and efficient PCOS management to promote reproductive health.

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References

  1. The Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41–7.

    Article  Google Scholar 

  2. Escobar-Morreale H. Polycystic ovary syndrome: definition, aetiology, diagnosis and treatment. Nat Rev Endocrinol. 2018;14:270–84.

    Article  PubMed  Google Scholar 

  3. Merkin SS, Phy JL, Sites CK, Yang D. Environmental determinants of polycystic ovary syndrome. Fertil Steril. 2016;106(1):16–24.

    Article  PubMed  Google Scholar 

  4. Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab. 2006;91:2100–4.

    Article  CAS  PubMed  Google Scholar 

  5. Day F, Karaderi T, Jones MR, Meun C, He C, Drong A, et al. Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLoS Genet. 2018;14(12):e1007813.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Rodriguez Paris V, Bertoldo MJ. The mechanism of androgen actions in PCOS etiology. Med Sci (Basel). 2019;7(9):89.

    Google Scholar 

  7. Schuebel K, Gitik M, Domschke K, Goldman D. Making sense of epigenetics. Int J Neuropsychopharmacol. 2016;19(11):58. https://doi.org/10.1093/ijnp/pyw058.

    Article  CAS  Google Scholar 

  8. Li Y, Tollefsbol TO. DNA methylation detection: bisulfite genomic sequencing analysis. Methods Mol Biol. 2011;791:11–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Motta AB. Epigenetic marks in polycystic ovary syndrome. Curr Med Chem. 2019. https://doi.org/10.2174/0929867326666191003154548.

    Article  PubMed  Google Scholar 

  10. Vázquez-Martínez ER, Gómez-Viais YI, García-Gómez E, Reyes-Mayoral C, Reyes-Muñoz E, Camacho-Arroyo I, Cerbón M. DNA methylation in the pathogenesis of polycystic ovary syndrome. Reproduction. 2019;158(1):R27–R40.

    Article  PubMed  Google Scholar 

  11. Rosenfield RL, Ehrmann DA. The pathogenesis of polycystic ovary syndrome (PCOS): the hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016;37(5):467–520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Abbott DH, Dumesic DA, Franks S. Developmental origin of polycystic ovary syndrome—a hypothesis. J Endocrinol. 2002;174(1):1–5.

    Article  CAS  PubMed  Google Scholar 

  13. Gur EB, Karadeniz M, Turan GA. Fetal programming of polycystic ovary syndrome. World J Diabetes. 2015;6(7):936–42.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Abbott DH, Tarantal AF, Dumesic DA. Fetal, infant, adolescent and adult phenotypes of polycystic ovary syndrome in prenatally androgenized female rhesus monkeys. Am J Primatol. 2009;71(9):776–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Xu N, Kwon S, Abbott DH, Geller DH, Dumesic DA, Azziz R, Guo X, Goodarzi MO. Epigenetic mechanism underlying the development of polycystic ovary syndrome (PCOS)-like phenotypes in prenatally androgenized rhesus monkeys. PLoS ONE. 2011;6(11):e27286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hogg K, McNeilly AS, Duncan WC. Prenatal androgen exposure leads to alterations in gene and protein expression in the ovine fetal ovary. Endocrinology. 2011;152(5):2048–59.

    Article  CAS  PubMed  Google Scholar 

  17. Connolly F, Rae MT, Späth K, Boswell L, McNeilly AS, Duncan WC. In an ovine model of polycystic ovary syndrome (PCOS) prenatal androgens suppress female fetal renal gluconeogenesis. PLoS ONE. 2015;10(7):e0132113.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Ramaswamy S, Grace C, Mattei A, et al. Developmental programming of polycystic ovary syndrome (PCOS): prenatal androgens establish pancreatic islet α/β cell ratio and subsequent insulin secretion. Sci Rep. 2016;6:27408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang F, Yu B, Yang W, Liu J, Lu J, Xia X. Polycystic ovary syndrome resembling histopathological alterations in ovaries from prenatal androgenized female rats. J Ovarian Res. 2012;5(1):15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nilsson E, Larsen G, Manikkam M, Guerrero-Bosagna C, Savenkova MI, Skinner MK. Environmentally induced epigenetic transgenerational inheritance of ovarian disease. PLoS ONE. 2012;7(5):e36129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hague WM, Adams J, Rodda C, Brook CG, de Bruyn R, Grant DB, Jacobs HS. The prevalence of polycystic ovaries in patients with congenital adrenal hyperplasia and their close relatives. Clin Endocrinol (Oxf). 1990;33(4):501–10.

    Article  CAS  Google Scholar 

  22. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995;80(12):3689–98.

    CAS  PubMed  Google Scholar 

  23. Kallak TK, Hellgren C, Skalkidou A, Sandelin-Francke L, Ubhayasekhera K, Bergquist J, Axelsson O, Comasco E, Campbell RE, Sundström PI. Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain. Eur J Endocrinol. 2017;177(4):379–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Barrett ES, Parlett LE, Sathyanarayana S, et al. Prenatal exposure to stressful life events is associated with masculinized anogenital distance (AGD) in female infants. Physiol Behav. 2013;114–115:14–20.

    Article  PubMed  CAS  Google Scholar 

  25. Sagvekar P, Kumar P, Mangoli V, Desai S, Mukherjee S. DNA methylome profiling of granulosa cells reveals altered methylation in genes regulating vital ovarian functions in polycystic ovary syndrome. Clin Epigenetics. 2019;11(1):61.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Li Z, Huang H. Epigenetic abnormality: a possible mechanism underlying the fetal origin of polycystic ovary syndrome. Med Hypotheses. 2008;70:638–42.

    Article  PubMed  Google Scholar 

  27. Franks S, Berga SL. Does PCOS have developmental origins? Fertil Steril. 2012;97(1):2–6.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Gilbert EW, Tay CT, Hiam DS, Teede HJ, Moran LJ. Comorbidities and complications of polycystic ovary syndrome: an overview of systematic reviews. Clin Endocrinol (Oxf). 2018;89(6):683–99.

    Article  Google Scholar 

  29. De Leo V, Musacchio MC, Palermo V, Di Sabatino A, Morgante G, Petraglia F. Polycystic ovary syndrome and metabolic comorbidities: therapeutic options. Drugs Today (Barc). 2009;45(10):763–75.

    Article  Google Scholar 

  30. Li R, Yu G, Yang D, Li S, Lu S, Wu X, Wei Z, Song X, Wang X, Fu S, Qiao J. Prevalence and predictors of metabolic abnormalities in Chinese women with PCOS: a cross-sectional study. BMC Endocr Disord. 2014;14:76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Wang XX, Wei JZ, Jiao J, Jiang SY, Yu DH, Li D. Genome-wide DNA methylation and gene expression patterns provide insight into polycystic ovary syndrome development. Oncotarget. 2014;5(16):6603–10.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Li S, Zhu D, Duan H, Ren A, Glintborg D, Andersen M, Skov V, Thomassen M, Kruse T, Tan Q. Differential DNA methylation patterns of polycystic ovarian syndrome in whole blood of Chinese women. Oncotarget. 2017;8(13):20656–66.

    Article  PubMed  Google Scholar 

  33. Shen HR, Qiu LH, Zhang ZQ, Qin YY, Cao C, Di W. Genome-wide methylated DNA immunoprecipitation analysis of patients with polycystic ovary syndrome. PLoS ONE. 2013;8(5):e64801.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Nilsson E, Benrick A, Kokosar M, Krook A, Lindgren E, Källman T, Martis MM, Højlund K, Ling C, Stener-Victorin E. Transcriptional and epigenetic changes influencing skeletal muscle metabolism in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2018;103(12):4465–77.

    Article  PubMed  Google Scholar 

  35. Glintborg D, Hass Rubin K, Nybo M, Abrahamsen B, Andersen M. Morbidity and medicine prescriptions in a nationwide Danish population of patients diagnosed with polycystic ovary syndrome. Eur J Endocrinol. 2015;172:627–38.

    Article  CAS  PubMed  Google Scholar 

  36. Janssen OE, Mehlmauer N, Hahn S, Offner AH, Gärtner R. High prevalence of autoimmune thyroiditis in patients with polycystic ovary syndrome. Eur J Endocrinol. 2004;150:363–9.

    Article  CAS  PubMed  Google Scholar 

  37. Du D, Li X. The relationship between thyroiditis and polycystic ovary syndrome: a meta-analysis. Int J Clin Exp Med. 2013;25(6):880–9.

    Google Scholar 

  38. Gaberšček S, Zaletel K, Schwetz V, Pieber T, Obermayer-Pietsch B, Lerchbaum E. Mechanisms in endocrinology: thyroid and polycystic ovary syndrome. Eur J Endocrinol. 2015;172:R9–21.

    Article  PubMed  CAS  Google Scholar 

  39. Arora S, Sinha K, Kolte S, Mandal A. Endocrinal and autoimmune linkage: evidences from a controlled study of subjects with polycystic ovarian syndrome. J Hum Reprod Sci. 2016;9:18–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mobeen H, Afzal N, Kashif M. Polycystic ovary syndrome may be an autoimmune disorder. Scientifica (Cairo). 2016;2016:4071735.

    Google Scholar 

  41. Bouchard P, Fauser BC. PCOS: an heterogeneous condition with multiple faces for multiple doctors. Eur J Endocrinol. 2014;171(4):E1–2.

    Article  CAS  PubMed  Google Scholar 

  42. Zhang HY, Guo CX, Zhu FF, Qu PP, Lin WJ, Xiong J. Clinical characteristics, metabolic features, and phenotype of Chinese women with polycystic ovary syndrome: a large-scale case–control study. Arch Gynecol Obstet. 2013;287:525–31.

    Article  PubMed  Google Scholar 

  43. Escobar-Morreale HF, Samino S, Insenser M, Vinaixa M, Luque-Ramírez M, Lasunción MA, Correig X. Metabolic heterogeneity in polycystic ovary syndrome is determined by obesity: plasma metabolomic approach using GC-MS. Clin Chem. 2012;58:999–1009.

    Article  CAS  PubMed  Google Scholar 

  44. Jacobsen VM, Li S, Wang A, Zhu D, Liu M, Thomassen M, Kruse T, Tan Q. Epigenetic association analysis of clinical sub-phenotypes in patients with polycystic ovary syndrome (PCOS). Gynecol Endocrinol. 2019;35(8):691–4.

    Article  CAS  PubMed  Google Scholar 

  45. Jones MR, Brower MA, Xu N, Cui J, Mengesha E, Chen YDI, et al. Systems genetics reveals the functional context of PCOS loci and identifies genetic and molecular mechanisms of disease heterogeneity. PLoS Genet. 2015;11(8):1005455.

    Article  CAS  Google Scholar 

  46. Tan Q. Harnessing the power of twins in epigenetic association studies: causal inference and more. Epigenomics. 2020;12(1):1–3.

    Article  CAS  PubMed  Google Scholar 

  47. Engmann L, Jin S, Sun F, Legro RS, Polotsky AJ, Hansen KR, Coutifaris C, Diamond MP, Eisenberg E, Zhang H, Santoro N. Racial and ethnic differences in the polycystic ovary syndrome metabolic phenotype. Am J Obstet Gynecol. 2017;216(5):493.e1–493.e13.

    Article  Google Scholar 

  48. Skov V, Glintborg D, Knudsen S, Jensen T, Kruse TA, Tan Q, Brusgaard K, Beck-Nielsen H, Højlund K. Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. Diabetes. 2007;56(9):2349–55.

    Article  CAS  PubMed  Google Scholar 

  49. Rush CJ, Campbell RT, Jhund PS, Petrie MC, McMurray JJV. Association is not causation: treatment effects cannot be estimated from observational data in heart failure. Eur Heart J. 2018;39(37):3417–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Listl S, Jurges H, Watt RG. Causal inference from observational data. Community Dent Oral Epidemiol. 2016;44(5):409–15.

    Article  PubMed  Google Scholar 

  51. Nguyen MH, Yang HI, Le A, et al. Reduced incidence of hepatocellular carcinoma in cirrhotic and noncirrhotic patients with chronic hepatitis B treated with tenofovir—a propensity score-matched study. J Infect Dis. 2019;219(1):10–8.

    Article  CAS  PubMed  Google Scholar 

  52. Dite GS, Gurrin LC, Byrnes GB, et al. Predictors of mammographic density: insights gained from a novel regression analysis of a twin study. Cancer Epidemiol Biomarkers Prev. 2008;17(12):3474–81.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Li S, Wong EM, Bui M, Nguyen TL, Joo JE, Stone J, Dite GS, Giles GG, Saffery R, Southey MC, Hopper JL. Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study. Clin Epigenet. 2018;10:18.

    Article  CAS  Google Scholar 

  54. Li S, Wong EM, Bui M, Nguyen TL, Joo JE, Stone J, Dite GS, Dugué PA, Milne RL, Giles GG, Saffery R, Southey MC, Hopper JL. Inference about causation between body mass index and DNA methylation in blood from a twin family study. Int J Obes (Lond). 2019;43(2):243–52.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Epidemiology and Biostatistics, Department of Public Health, University of Southern Denmark, Odense, Denmark

    Qihua Tan

  2. Department of Clinical Research, Unit of Human Genetics, University of Southern Denmark, J. B. Winsløws Vej 9B, 5000, Odense C, Denmark

    Qihua Tan

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  1. Qihua Tan
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Correspondence to Qihua Tan.

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The author (QT) declares that no competing interests exist.

Funding

This study was supported by the Independent Research Fund Denmark (Grant number DFF-6110-00114).

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Tan, Q. Deciphering the DNA Methylome of Polycystic Ovary Syndrome. Mol Diagn Ther 24, 245–250 (2020). https://doi.org/10.1007/s40291-020-00463-w

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