A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese

Satoko Uno, Hitoshi Zembutsu, Akira Hirasawa, Atsushi Takahashi, Michiaki Kubo, Tomoko Akahane, Daisuke Aoki, Naoyuki Kamatani, Koichi Hirata, Yusuke Nakamura
Nature genetics · 2010 · vol. 42(8) , pp. 707–710 · doi:10.1038/ng.612 · PMID:20601957 · W2004242608
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A genome-wide association study in Japanese individuals identified a significant association between endometriosis and genetic variants in the CDKN2BAS locus on chromosome 9p21.

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This paper conducted a genome-wide association study with replication in 1,907 Japanese women with endometriosis and 5,292 controls to identify genetic susceptibility variants. The study found a significant association at rs10965235 in the CDKN2BAS locus on chromosome 9p21, with fine-mapping suggesting the variant affects regulation of p15, p16, and p14 expression; rs16826658 in an LD block including WNT4 on chromosome 1p36 showed a possible additional association. A key caveat explicitly stated is that the findings suggest new susceptibility loci but do not fully establish causal mechanisms beyond gene-regulatory implications. This paper is centrally about endometriosis — it reports GWAS evidence implicating the CDKN2BAS locus and a possible WNT4-related signal in Japanese endometriosis susceptibility.

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Abstract

Although the pathogenesis of endometriosis is not well understood, genetic factors have been considered to have critical roles in its etiology. Through a genome-wide association study and a replication study using a total of 1,907 Japanese individuals with endometriosis (cases) and 5,292 controls, we identified a significant association of endometriosis with rs10965235 (P = 5.57 × 10−12, odds ratio = 1.44), which is located in CDKN2BAS on chromosome 9p21, encoding the cyclin-dependent kinase inhibitor 2B antisense RNA. By fine mapping, the SNP showing the strongest association was located in intron 16 of CDKN2BAS and was implicated in regulating the expression of p15, p16 and p14. A SNP, rs16826658, in the LD block including WNT4 on chromosome 1p36, which is considered to play an important role in the development of the female genital tract, revealed a possible association with endometriosis (P = 1.66 × 10−6, odds ratio = 1.20). Our findings suggest that these regions are new susceptibility loci for endometriosis. This is a preview of subscription content, access via your institution Access options Subscribe to this journal Receive 12 print issues and online access 251,40 € per year only 20,95 € per issue Buy this article - Purchase on SpringerLink - Instant access to the full article PDF. 39,95 € Prices may be subject to local taxes which are calculated during checkout Similar content being viewed by others

References

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Acknowledgements

We thank the members of the Rotary Club of Osaka-Midosuji District 2660 Rotary International in Japan for supporting our study. We also thank the technical staff of the Laboratory for Genotyping Development in RIKEN, Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo and Department of Obstetrics and Gynecology, Keio University, School of Medicine. This work was conducted as a part of the BioBank Japan Project that was supported by the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government. Author information Authors and Affiliations Contributions Y.N. conceived the study. Y.N., H.Z., S.U., K.H. and M.K. designed the study. S.U., T.A. and M.K. performed genotyping. S.U., A.T., N.K. and M.K. performed the data analyses. Y.N., H.Z., and M.K. managed DNA samples belonging to BioBank Japan. A.H. and D.A. managed DNA samples belonging to Keio University. S.U. summarized the results. S.U., H.Z. and Y.N. wrote the manuscript. Y.N. obtained funding for the study. Corresponding author Ethics declarations Competing interests The authors declare no competing financial interests. Supplementary information Supplementary Text and Figures (download PDF ) Supplementary Figure 1 and Supplementary Tables 1–3 (PDF 666 kb) Rights and permissions About this article Cite this article Uno, S., Zembutsu, H., Hirasawa, A. et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet 42, 707–710 (2010). https://doi.org/10.1038/ng.612 Received: Accepted: Published: Issue date: DOI: https://doi.org/10.1038/ng.612 This article is cited by - Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes Scientific Reports (2021) - GWAS of five gynecologic diseases and cross-trait analysis in Japanese European Journal of Human Genetics (2020) - Endometriosis, endocrine disrupters, and epigenetics: an investigation into the complex interplay in women with polybrominated biphenyl exposure and endometriosis Journal of Assisted Reproduction and Genetics (2020) - Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis Nature Communications (2019) - Japanese GWAS identifies variants for bust-size, dysmenorrhea, and menstrual fever that are eQTLs for relevant protein-coding or long non-coding RNAs Scientific Reports (2018)

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mesh:D004715endometriosis

MeSH descriptors

Asian People Cyclin-Dependent Kinase Inhibitor p15 Genome-Wide Association Study RNA, Antisense Adult Asian People Cyclin-Dependent Kinase Inhibitor p15 Disease Susceptibility Endometriosis Endometriosis Female Genes Humans Middle Aged Polymorphism, Single Nucleotide RNA, Antisense

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