Pathogenesis of Endometriosis: Genetics

Endometriosis is a complex condition that is caused by both multiple genetic and environmental factors. The heritable component for endometriosis is estimated at ~50%. Here we provide a summary of genome-wide associations studies (GWAS) performed to date to identify common genetic variants for endometriosis. Largest GWAS meta-analysis conducted by the International Endogene Genomics Consortium (IEGC) included a total of 58,115 endometriosis cases and 733,480 controls and has identified 27 loci genome-wide significantly associated with endometriosis. Positionally, the lead SNPs for the identified genetic loci reside near genes that are involved in sex-steroid hormone, WNT signaling, cell adhesion/migration, cell growth/carcinogenesis, and inflammation-related pathways. Furthermore, genetic variants associated with subtypes of endometriosis are described. In particular, eight genome-wide significant signals were associated with stage III/IV disease and 21 of 27 loci had larger effect sizes in stage III/IV disease compared to stage I/II disease suggesting that particular variants may confer risk for different subtypes of endometriosis through different pathways. Together, the 27 loci explained 2.15% of variance for overall endometriosis and 3.83% for stage III/IV disease which highlight that there remain many more genetic loci to be revealed for endometriosis in larger, deeply phenotyped datasets. Furthermore, future research needs to focus on fine-mapping of the identified loci to reveal the causal variants for each of the 27 loci and functional follow-up examining their effects on multiomics data in tissues and cells relevant to endometriosis, i.e., endometrium and its cellular components. Access this chapter Tax calculation will be finalised at checkout Purchases are for personal use only Similar content being viewed by others

Craig J. Complex diseases: research and applications. Nat Educ. 2008;1(1):184. Saha R, Pettersson HJ, Svedberg P, Olovsson M, Bergqvist A, Marions L, Tornvall P, Kuja-Halkola R. Heritability of endometriosis. Fertil Steril. 2015;104:947–52. Treloar SA, O’Connor DT, O’Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. [email protected]. Fertil Steril. 1999;71:701–10. Lee SH, Harold D, Nyholt DR, Goddard ME, Zondervan KT, Williams J; Consortium, A.N., International Endogene, C., Genetic, Environmental Risk for Alzheimer’s disease, C., et al. Estimation and partitioning of polygenic variation captured by common SNPs for Alzheimer’s disease, multiple sclerosis and endometriosis. Hum Mol Genet. 2013;22:832–41. Rahmioglu N, Missmer SA, Montgomery GW, Zondervan KT. Insights into assessing the genetics of endometriosis. Curr Obstet Gynecol Rep. 2012;1:124–37. Zondervan KT, Cardon LR. Designing candidate gene and genome-wide case-control association studies. Nat Protoc. 2007;2:2492–501. Adachi S, Tajima A, Quan J, Haino K, Yoshihara K, Masuzaki H, Katabuchi H, Ikuma K, Suginami H, Nishida N, et al. Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. J Hum Genet. 2010;55:816–21. Uno S, Zembutsu H, Hirasawa A, Takahashi A, Kubo M, Akahane T, Aoki D, Kamatani N, Hirata K, Nakamura Y. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet. 2010;42:707–10. Painter JN, Anderson CA, Nyholt DR, Macgregor S, Lin J, Lee SH, Lambert A, Zhao ZZ, Roseman F, Guo Q, et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet. 2011;43:51–4. Albertsen HM, Chettier R, Farrington P, Ward K. Genome-wide association study link novel loci to endometriosis. PLoS One. 2013;8:e58257. Nyholt DR, Low SK, Anderson CA, Painter JN, Uno S, Morris AP, MacGregor S, Gordon SD, Henders AK, Martin NG, et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet. 2012;44:1355–9. Steinthorsdottir V, Thorleifsson G, Aradottir K, Feenstra B, Sigurdsson A, Stefansdottir L, Kristinsdottir AM, Zink F, Halldorsson GH, Munk Nielsen N, et al. Common variants upstream of KDR encoding VEGFR2 and in TTC39B associate with endometriosis. Nat Commun. 2016;7:12350. Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I, Buring JE, Zhang F, Edwards TL, Jones S, et al. Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism. Nat Commun. 2017;8:15539. Sobalska-Kwapis M, Smolarz B, Slomka M, Szaflik T, Kepka E, Kulig B, Siewierska-Gorska A, Polak G, Romanowicz H, Strapagiel D, et al. New variants near RHOJ and C2, HLA-DRA region and susceptibility to endometriosis in the Polish population-The genome-wide association study. Eur J Obstet Gynecol Reprod Biol. 2017;217:106–12. Galarneau G, Fontanillas P, Clementi C, Hu-Seliger T, Parfitt DE, Tung JY, Yurttas-Beim P; the Celmatix Research Team; the 23andMe Research Team. Genome-wide association studies on endometriosis and endometriosis related infertility. BioRxiv. 2018. Rahmioglu N, Banasik K, Christofidou P, Danning R, Galarneau G, Giri A, MacGregor S, Mortlock S, Sapkota Y, Schork JA, et al. Large-scale genome-wide association meta-analysis of endometriosis reveals 13 novel loci and genetically-associated comorbidity with other pain conditions. BioRxiv. 2018. Powell JE, Fung JN, Shakhbazov K, Sapkota Y, Cloonan N, Hemani G, Hillman KM, Kaufmann S, Luong HT, Bowdler L, et al. Endometriosis risk alleles at 1p36.12 act through inverse regulation of CDC42 and LINC00339. Hum Mol Genet. 2016;25:5046–58. Consortium, G.T. Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648–60. Consortium, G.T., Laboratory, D.A., Coordinating Center-Analysis Working, G., Statistical Methods Groups-Analysis Working, G., Enhancing, G.g., Fund, N.I.H.C., NIH/NCI, NIH/NHGRI, NIH/NIMH, NIH/NIDA, et al. Genetic effects on gene expression across human tissues. Nature. 2017;550:204–13. Fung JN, Mortlock S, Girling JE, Holdsworth-Carson SJ, Teh WT, Zhu Z, Lukowski SW, McKinnon BD, McRae A, Yang J, et al. Genetic regulation of disease risk and endometrial gene expression highlights potential target genes for endometriosis and polycystic ovarian syndrome. Sci Rep. 2018;8:11424. Mortlock S, Kendarsari RI, Fung JN, Gibson G, Yang F, Restuadi R, Girling JE, Holdsworth-Carson SJ, Teh WT, Lukowski SW, et al. Tissue specific regulation of transcription in endometrium and association with disease. Hum Reprod. 2020;35:377–93. Becker CM, Laufer MR, Stratton P, Hummelshoj L, Missmer SA, Zondervan KT, Adamson GD, Group, W.E.W. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: I. Surgical phenotype data collection in endometriosis research. Fertil Steril. 2014;102:1213–22. Fassbender A, Rahmioglu N, Vitonis AF, Vigano P, Giudice LC, D’Hooghe TM, Hummelshoj L, Adamson GD, Becker CM, Missmer SA, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project: IV. Tissue collection, processing, and storage in endometriosis research. Fertil Steril. 2014;102:1244–53. Rahmioglu N, Fassbender A, Vitonis AF, Tworoger SS, Hummelshoj L, D’Hooghe TM, Adamson GD, Giudice LC, Becker CM, Zondervan KT, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: III. Fluid biospecimen collection, processing, and storage in endometriosis research. Fertil Steril. 2014;102:1233–43. Vitonis AF, Vincent K, Rahmioglu N, Fassbender A, Buck Louis GM, Hummelshoj L, Giudice LC, Stratton P, Adamson GD, Becker CM, et al. World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project: II. Clinical and covariate phenotype data collection in endometriosis research. Fertil Steril. 2014;102:1223–32. Author information Authors and Affiliations Corresponding author Editor information Editors and Affiliations Rights and permissions Copyright information © 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG About this chapter Cite this chapter Rahmioglu, N., Zondervan, K.T. (2022). Pathogenesis of Endometriosis: Genetics. In: Oral, E. (eds) Endometriosis and Adenomyosis. Springer, Cham. https://doi.org/10.1007/978-3-030-97236-3_6 Download citation DOI: https://doi.org/10.1007/978-3-030-97236-3_6 Published: Publisher Name: Springer, Cham Print ISBN: 978-3-030-97235-6 Online ISBN: 978-3-030-97236-3 eBook Packages: MedicineMedicine (R0)