Molecular Genetics of Endometriosis

Jodie N Painter, Queensland Institute of Medical Research, Brisbane, Australia
Krina T Zondervan, University of Oxford, Oxford, UK
Stacey A Missmer, Brigham and Women's Hospital and Harvard Schools of Medicine and Public Health, Boston, Massachusetts, USA
Grant W Montgomery, Queensland Institute of Medical Research, Brisbane, Australia

Published online: September 2011

DOI: 10.1002/9780470015902.a0021473

Endometriosis is a gynaecological disease that affects 6–10% of women of reproductive age. Symptoms vary but commonly include severe menstrual and pelvic pain and infertility, all of which can have major impacts on the lives of affected women. Linkage studies have identified several chromosomal regions but the genes contributing to these linkage signals have yet to be identified. Candidate gene studies on over 80 genes have not shown robust evidence of association, mostly due to the limited power to detect individual risk variants of small effects. Four groups have now conducted genome-wide association studies for endometriosis, revealing a number of intriguing candidates that may contribute to disease risk. Further research aimed at increasing our understanding of the genes and biological pathways underlying endometriosis may provide better and more targeted diagnosis and treatment options in the future.

Key Concepts:

  • Endometriosis is a gynaecological disease that occurs when tissue resembling endometrium (the tissue that lines the inside of the uterus) attaches and grows on organs in the body cavity, including the ovaries, fallopian tubes, intestine and bowel.
  • Endometriosis affects 6–10% of women during their reproductive years and the symptoms, including severe menstrual and pelvic pain and sub- or infertility, can greatly impact an affected woman's physical and psychological wellbeing as well as her family and working life.
  • The financial cost of endometriosis is amongst the highest of all complex diseases, with direct (medical and surgical treatment) and indirect (loss of income, reduced productivity, infertility treatment and social withdrawal) health care costs estimated at >$15 billion annually in the US alone.
  • Linkage studies on large numbers of families have indicated chromosomal regions that may harbour endometriosis susceptibility genes but these are yet to be definitively identified.
  • Candidate gene association studies on over 80 genes have not produced convincing evidence of gene robustly associated with endometriosis susceptibility.
  • Genome-wide association studies have identified a small number of chromosomal areas that harbour extremely interesting candidate genes that should be followed up in the future.
  • Understanding the genes and biological pathways underlying susceptibility to endometriosis may eventually lead to better diagnostic and treatment options for women affected by this common and often debilitating disease.

Keywords: genetics; gene mapping; candidate genes; linkage; genome-wide association; endometriosis

Figure 1. Genome-wide association results for the discovery sample including 3194 endometriosis cases and 7060 controls of European ancestry (Painter et al., 2011a). The P-value for our best ‘hit’ on chromosome 7 reached genome-wide significance (P<5.8×10–8) when the replication sample was included in the analysis.
Figure 2. SNAP plot of genome-wide association results for chromosome 1 around the WNT4 gene (Painter et al., 2011a). Our results replicated signal from a Japanese endometriosis GWAS (Uno et al., 2010): the red colour indicates the level of linkage disequilibrium in Caucasians between GWA SNPs in the region and the replicated SNP rs7521902. (SNAP plot created using http://www.broadinstitute.org/mpg/snap/ldplot.php.)
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 References
    Adachi S, Tajima A, Quan J et al. (2010) Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. Journal of Human Genetics 55: 816–821.
    ePath Albertsen H, French G, Dintelman S et al. (2009) Genome-wide Association Study Identifies Novel Loci Associated with Endometriosis in A Caucasian Population. American Society of Human Genetic Hawaii. http://www.juneaubiosciences.com/About_Us_Presentations_Endometriosis_and_Preterm_Labor_Research_files/Albertsen_ASHG_Poster1024.pdf.
    American Fertility Society (1985) Revised American Fertility Society classification of endometriosis: 1985. Fertility and Sterility 43: 351–352.
    Aulchenko YS, Ripatti S, Lindqvist SI et al. (2009) Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nature Genetics 41: 47–55.
    Bodmer W and Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nature Genetics 40: 695–701.
    Boyer A, Lapointe E, Zheng X et al. (2010) WNT4 is required for normal ovarian follicle development and female fertility. The FASEB Journal 24: 3010–3025.
    Bozdag GA, Alp Z, Saribas S et al. (2010) CYP17 and CYP2C19 gene polymorphisms in patients with endometriosis. Reproductive Biomedicine Online 20: 286–290.
    Brinton L, Gridley G, Persson I et al. (1997) Cancer risk after a hospital discharge diagnosis of endometriosis. American Journal of Obstetrics and Gynecology 176: 572–579.
    Cayan F, Ayaz L, Aban M et al. (2009) Role of CYP2C19 polymorphisms in patients with endometriosis. Gynecological Endocrinology 25: 530–535.
    Cribb AE, Knight MJ, Dryer D et al. (2006) Role of polymorphic human cytochrome P450 enzymes in estrone oxidation. Cancer Epidemiology, Biomarkers and Prevention 15: 551–558.
    Falconer H, D'Hooghe T and Fried G (2007) Endometriosis and genetic polymorphisms. Obstetrics and Gynecological Surveys 62: 616–628.
    Gao X, Outley J, Botteman M et al. (2006) Economic burden of endometriosis. Fertility and Sterility 86: 1561–1572.
    Gorlov IP, Gorlova OY, Sunyaev SR, Spitz MR and Amos CI, (2008) Shifting paradigm of association studies: value of rare single-nucleotide polymorphisms. American Journal of Human Genetics 82: 100–112.
    Guo SW (2005) Glutathione S-transferases M1/T1 gene polymorphisms and endometriosis: a meta-analysis of genetic association studies. Molecular Human Reproduction 11: 729–743.
    Guo SW (2006a) The association of endometriosis risk and genetic polymorphisms involving dioxin detoxification enzymes: a systematic review. European Journal of Obstetrics, Gynecology and Reproductive Biology 124: 134–143.
    Guo SW (2006b) Association of endometriosis risk and genetic polymorphisms involving sex steroid biosynthesis and their receptors: a meta-analysis. Gynecologic and Obstetric Investigation 61: 90–105.
    Hindorff LA, Sethupathy P, Junkins HA et al. (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of the USA 106: 9362–9367.
    Ioannidis JP, Ntzani EE, Trikalinos TA and Contopoulos-Ioannidis DG (2001) Replication validity of genetic association studies. Nature Genetics 29: 306–309.
    Justenhoven C, Hamann U, Pierl CB et al. (2009) CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Research and Treatment 115: 391–396.
    Kennedy S, Mardon H and Barlow D (1995) Familial endometriosis. Journal of Assisted Reproduction and Genetics 12: 32–34.
    Kondera-Anasz Z, Sikora J, Mielczarek-Palacz A and Jonca M (2005) Concentrations of interleukin (IL)-1alpha, IL-1 soluble receptor type II (IL-1 sRII) and IL-1 receptor antagonist (IL-1 Ra) in the peritoneal fluid and serum of infertile women with endometriosis. European Journal of Obstetrics, Gynecology and Reproductive Biology 123: 198–203.
    Kvaskoff M, Mesrine S, Fournier A et al. (2007) Personal history of endometriosis and risk of cutaneous melanoma in a large prospective cohort of French women. Archives of Internal Medicine 167: 2061–2065.
    Lee AJ, Cai MX, Thomas PE et al. (2003) Characterization of the oxidative metabolites of 17beta-estradiol and estrone formed by 15 selectively expressed human cytochrome p450 isoforms. Endocrinology 144: 3382–3398.
    McCarthy MI, Abecasis GR, Cardon LR et al. (2008) Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics 9: 356–369.
    Montgomery GW, Nyholt DR, Zhao ZZ et al. (2008) The search for genes contributing to endometriosis risk. Human Reproduction Update 14: 447–457.
    Mwinyi J, Cavaco I, Pedersen RS et al. (2010) Regulation of CYP2C19 expression by estrogen receptor alpha: implications for estrogen-dependent inhibition of drug metabolism. Molecular Pharmacology 78: 886–894.
    Naillat F, Prunskaite-Hyyrylainen R, Pietila I et al. (2010) Wnt4/5a signalling coordinates cell adhesion and entry into meiosis during presumptive ovarian follicle development. Human Molecular Genetics 19: 1539–1550.
    Nejentsev S, Walker N, Riches D et al. (2009) Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324: 387–389.
    Nyholt DR, Gillespie NG, Merikangas KR et al. (2009) Common genetic influences underlie comorbidity of migraine and endometriosis. Genetic Epidemiology 33: 105–113.
    Painter JN, Anderson CA, Nyholt DR et al. (2011a) Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nature Genetics 43: 51–54.
    Painter JN, Nyholt DR, Morris A et al. (2011b) High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19. Fertility and Sterility 95: 2236–2240.
    Purcell SM, Wray NR, Stone JL et al. (2009) Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 460: 748–752.
    Rier SE, Martin DC, Bowman RE and Becker JL (1995) Immunoresponsiveness in endometriosis: implications of estrogenic toxicants. Environmental Health Perspectives 103(Suppl 7): 151–156.
    Risch N (1990) Linkage strategies for genetically complex traits. II. The power of affected relative pairs. American Journal of Human Genetics 46: 229–241.
    Simpson JL and Bischoff FZ (2002) Heritability and molecular genetic studies of endometriosis. Annals of the New York Academy of Sciences 955: 239–251.
    Stefansson H, Geirsson RT, Steinthorsdottir V et al. (2002) Genetic factors contribute to the risk of developing endometriosis. Human Reproduction 17: 555–559.
    Tempfer CB, Simoni M, Destenaves B and Fauser BCJM (2009) Functional genetic polymorphisms and female reproductive disorders: part II – endometriosis. Human Reproduction Update 15: 97–118.
    Treloar S, Hadfield R, Montgomery G et al. (2002) The International Endogene Study: a collection of families for genetic research in endometriosis. Fertility and Sterility 78: 679–685.
    Treloar SA, Bell TA, Nagle CM et al. (2010) Early menstrual characteristics associated with subsequent diagnosis of endometriosis. American Journal of Obstetrics and Gynecology 202: 534. e1-6.
    Treloar SA, O'Conner DT, O'Conner VM and Martin NG (1999) Genetic influences on endometriosis in an Australian twin sample. Fertility and Sterility 17: 701–710.
    Treloar SA, Wicks J, Nyholt DR et al. (2005a) Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26. American Journal of Human Genetics 77: 365–376.
    Treloar SA, Zhao ZZ, Armitage T et al. (2005b) Association between polymorphisms in the progesterone receptor gene and endometriosis. Molecular Human Reproduction 11: 641–647.
    Treloar SA, Zhao ZZ, Le L et al. (2007) Variants in EMX2 and PTEN do not contribute to risk of endometriosis. Molecular Human Reproduction 13: 587–594.
    Uno S, Zembutsu H, Hirasawa A et al. (2010) A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nature Genetics 42: 707–710.
    Varma R, Rollason T, Gupta JK and Maher ER (2004) Endometriosis and the neoplastic process. Reproduction 127: 293–304.
    Visscher PM and Montgomery GW (2009) Genome-wide association studies and human disease: from trickle to flood. The Journal of the American Medical Association 302: 2028–2029.
    Yang J, Benyamin B, McEvoy BP et al. (2010) Common SNPs explain a large proportion of the heritability for human height. Nature Genetics 42: 565–569.
    Zanatta A, Rocha AM, Carvalho FM et al. (2010) The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: a review. Journal of Assisted Reproduction and Genetics 27: 701–710.
    Zhao ZZ, Pollock PM, Thomas S et al. (2008) Common variation in the fibroblast growth factor receptor 2 gene is not associated with endometriosis risk. Human Reproduction 23: 1661–1668.
    Zondervan KT and Cardon LR (2004) The complex interplay among factors that influence allelic association. Nature Genetics Reviews 5: 89–100.
    Zondervan KT, Treloar SA, Lin J et al. (2007) Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian autosomal inheritance on chromosome 7p13–15. Human Reproduction 22: 717–728.
    Zondervan KT, Weeks DE, Colman R et al. (2004) Familial aggregation of endometriosis in a large pedigree of rhesus macaques. Human Reproduction 19: 448–455.
 Further Reading
    Lee SH, Wray NR, Goddard ME and Visscher PM (2011) Estimating missing heritability for disease from genome-wide association studies. American Journal of Human Genetics 88: 294–305.
    Yang J, Lee SH, Goddard ME and Visscher PM (2011) GCTA: a tool for genome-wide complex trait analysis. American Journal of Human Genetics 88: 76–82.

Related Sub-Topics:

Molecular Genetics of Common and Complex Disease | Specific Genetic Disorders | Linkage Analysis
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Article Title: Molecular Genetics of Endometriosis
 
How to Cite close
Painter, Jodie N, Zondervan, Krina T, Missmer, Stacey A, and Montgomery, Grant W(Sep 2011) Molecular Genetics of Endometriosis. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021473]