{"paper_id":"035ece3f-f83c-4b30-9e66-110565531fbb","body_text":"Abstract\nTo identify susceptibility genes for endometriosis in Japanese women, genome-wide association (GWA) analysis was performed using two case–control cohorts genotyped with the Affymetrix Mapping 500K Array or Genome-Wide Human SNP Array 6.0. In each of the two array cohorts, stringent quality control (QC) filters were applied to newly obtained genotype data, together with previously analyzed data from the Japanese Integrated Database Project. After QC-based filtering of samples and single nucleotide polymorphisms (SNPs) in each cohort, 282 838 SNPs in both genotyping platforms were tested for association with endometriosis using a meta-analysis of the two GWA studies with 696 patients with endometriosis and 825 controls. The meta-analysis revealed that a common susceptibility locus conferring a large effect on the disease risk was unlikely. On the other hand, an excess of SNPs with P-values <10−4 (36 vs 28 SNPs expected by chance) was observed in the meta-analysis. Of note, four of the top five SNPs with P-values <10−5 were located in and around IL1A (interleukin 1α), which might be a functional candidate gene for endometriosis. Further studies with larger case–control cohorts will be necessary to elucidate the genetic risk factors.\nSimilar content being viewed by others\nLog in or create a free account to read this content\nGain free access to this article, as well as selected content from this journal and more on nature.com\nor\nReferences\nGiudice, L. C. & Kao, L. C. Endometriosis. Lancet 364, 1789–1799 (2004).\nGao, X.,, Outley, J., Botteman, M., Spalding, J., Simon, J. A. & Pashos, C. L. Economic burden of endometriosis. Fertil. Steril. 86, 1561–1572 (2006).\nBulun, S. E. Endometriosis. N. Engl. J. Med. 360, 268–279 (2009).\nMontgomery, G. W., Nyholt, D. R., Zhao, Z. Z., Treloar, S. A., Painter, J. N., Missmer, S. A. et al. The search for genes contributing to endometriosis risk. Hum. Reprod. Update 14, 447–457 (2008).\nBerkley, K. J., Rapkin, A. J. & Papka, R. E. The pains of endometriosis. Science 308, 1587–1589 (2005).\nKennedy, S., Mardon, H. & Barlow, D. Familial endometriosis. J. Assist. Reprod. Genet. 12, 32–34 (1995).\nSimpson, J. L. & Bischoff, F. Z. Heritability and molecular genetic studies of endometriosis. Ann. NY Acad. Sci. 955, 239–251; discussion 293–295, 396–406 (2002).\nStefansson, H.,, Geirsson, R. T., Steinthorsdottir, V., Jonsson, H., Manolescu, A., Kong, A. et al. Genetic factors contribute to the risk of developing endometriosis. Hum. Reprod. 17, 555–559 (2002).\nTreloar, S.,, Hadfield, R., Montgomery, G., Lambert, A., Wicks, J., Barlow, D. H. et al. The International Endogene Study: a collection of families for genetic research in endometriosis. Fertil. Steril. 78, 679–685 (2002).\nTreloar, S. A., O’Connor, D. T., O’Connor, V. M. & Martin, N. G. Genetic influences on endometriosis in an Australian twin sample. sueT@qimr.edu.au. Fertil. Steril. 71, 701–710 (1999).\nSimpson, J. L., Elias, S., Malinak, L. R. & Buttram, V. C. Jr Heritable aspects of endometriosis. I. Genetic studies. Am. J. Obstet. Gynecol. 137, 327–331 (1980).\nKashima, K.,, Ishimaru, T., Okamura, H., Suginami, H., Ikuma, K., Murakami, T. et al. Familial risk among Japanese patients with endometriosis. Int. J. Gynaecol. Obstet. 84, 61–64 (2004).\nHadfield, R. M., Mardon, H. J., Barlow, D. H. & Kennedy, S. H. Endometriosis in monozygotic twins. Fertil. Steril. 68, 941–942 (1997).\nMoen, M. H. Endometriosis in monozygotic twins. Acta. Obstet. Gynecol. Scand. 73, 59–62 (1994).\nZondervan, K. T.,, Treloar, S. A., Lin, J., Weeks, D. E., Nyholt, D. R., Mangion, J. et al. Significant evidence of one or more susceptibility loci for endometriosis with near-Mendelian inheritance on chromosome 7p13-15. Hum. Reprod. 22, 717–728 (2007).\nTreloar, S. A.,, Zhao, Z. Z., Le, L., Zondervan, K. T., Martin, N. G., Kennedy, S. et al. Variants in EMX2 and PTEN do not contribute to risk of endometriosis. Mol. Hum. Reprod. 13, 587–594 (2007).\nPearson, T. A. & Manolio, T. A. How to interpret a genome-wide association study. JAMA 299, 1335–1344 (2008).\nKoike, A., Nishida, N., Inoue, I., Tsuji, S. & Tokunaga, K. Genome-wide association database developed in the Japanese Integrated Database Project. J. Hum. Genet. 54, 543–546 (2009).\nOtowa, T.,, Tanii, H., Sugaya, N., Yoshida, E., Inoue, K., Yasuda, S. et al. Genome-wide association study of panic disorder in the Japanese population. J. Hum. Genet. 54, 122–126 (2009).\nNishida, N.,, Koike, A., Tajima, A., Ogasawara, Y., Ishibashi, Y., Uehara, Y. et al. Evaluating the performance of Affymetrix SNP Array 6.0 platform with 400 Japanese individuals. BMC Genomics 9, 431 (2008).\nRabbee, N. A genotype calling algorithm for Affymetrix SNP arrays. Bioinformatics 22, 7–12 (2006).\nWellcome Trust Case Control Consortium. Genome-wide association study of 14 000 cases of seven common diseases and 3000 shared controls. Nature 447, 661–678 (2007).\nPurcell, S.,, Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A., Bender, D. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).\nYamaguchi-Kabata, Y.,, Nakazono, K., Takahashi, A., Saito, S., Hosono, N., Kubo, M. et al. Japanese population structure, based on SNP genotypes from 7003 individuals compared to other ethnic groups: effects on population-based association studies. Am. J. Hum. Genet. 83, 445–456 (2008).\nNakaoka, H. & Inoue, I. Meta-analysis of genetic association studies: methodologies, between-study heterogeneity and winner's curse. J. Hum. Genet. 54, 615–623 (2009).\nMantel, N. & Haenszel, W. Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst. 22, 719–748 (1959).\nIoannidis, J. P., Patsopoulos, N. A. & Evangelou, E. Heterogeneity in meta-analyses of genome-wide association investigations. PLoS One. 2, e841 (2007).\nBarrett, J. C., Fry, B., Maller, J. & Daly, M. J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).\nPurcell, S., Cherny, S. S. & Sham, P. C. Genetic power calculator: design of linkage and association genetic mapping studies of complex traits. Bioinformatics 19, 149–150 (2003).\nUno, S.,, Zembutsu, H., Hirasawa, A., Takahashi, A., Kubo, M., Akahane, T. 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).\nFitzgerald, K. A. Integr-ating IL-1 alpha in antiviral host defenses. Immunity 31, 7–9 (2009).\nKondera-Anasz, Z., Sikora, J., Mielczarek-Palacz, A. & Jonca, M. 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. Eur. J. Obstet. Gynecol. Reprod Biol. 123, 198–203 (2005).\nAcknowledgements\nAll women with endometriosis were registered at the Niigata University Hospital, the Nagasaki University Hospital, the Kumamoto University Hospital, the Takarazuka City Hospital, the National Hospital Organization Kyoto Medical Center, the Nagaoka Red Cross Hospital, the Kido Hospital, the Niigata Cancer Center Hospital, the Suibarago Hospital, the Joetsu General hospital, the Kaetsu Hospital, the Niigata Medical Center, the Muikamachi Hospital, the Toyama Red Cross Hospital and the Syonai Hospital. We thank Katsunori Kashima, Nobumichi Nishikawa, Naoki Fukui and Masayuki Yamaguchi for the management of DNA samples. We thank China Seki, Akemi Yukawa, Hiromi Kamura and Eriko Tokubo for their technical assistance. The data used for this research are partly available at the website of ‘DB Development for Medical Application from Disease Analysis (https://gwas.lifesciencedb.jp/index.html),’ which is a part of the ‘Integrated Database Project’ funded by the Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was supported, in part, by 2008 Research and Study Program of Tokai University Educational System General Research Organization (AT).\nAuthor information\nAuthors and Affiliations\nCorresponding authors\nAdditional information\nSupplementary Information accompanies the paper on Journal of Human Genetics website\nRights and permissions\nAbout this article\nCite this article\nAdachi, S., Tajima, A., Quan, J. et al. Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. J Hum Genet 55, 816–821 (2010). https://doi.org/10.1038/jhg.2010.118\nReceived:\nRevised:\nAccepted:\nPublished:\nIssue date:\nDOI: https://doi.org/10.1038/jhg.2010.118\nKeywords\nThis article is cited by\n-\nAPOBEC mediated mutagenesis drives genomic heterogeneity in endometriosis\nJournal of Human Genetics (2022)\n-\nIntegration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes\nScientific Reports (2021)\n-\nJapanese GWAS identifies variants for bust-size, dysmenorrhea, and menstrual fever that are eQTLs for relevant protein-coding or long non-coding RNAs\nScientific Reports (2018)\n-\nThe impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis\nMolecular Genetics and Genomics (2018)\n-\nA higher prevalence of endometriosis among Asian women does not contribute to poorer IVF outcomes\nJournal of Assisted Reproduction and Genetics (2017)","source_license":"CC0","license_restricted":false}