{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T12:04:34Z","timestamp":1774440274260,"version":"3.50.1"},"reference-count":33,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn\u2019s disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n\u2009=\u200920). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with <jats:italic>tenascin-XA<\/jats:italic> (<jats:italic>TNXA<\/jats:italic>) expression were significantly associated with CD in GWAS. By TWAS, <jats:italic>TNFSF15<\/jats:italic> (FDR\u2009=\u20091.35e-13) in whole blood, <jats:italic>ERV3-1<\/jats:italic> (FDR\u2009=\u20092.18e-2) in lymphocytes, and <jats:italic>ZNF713<\/jats:italic> (FDR\u2009=\u20093.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.<\/jats:p>","DOI":"10.1038\/s41598-020-66951-5","type":"journal-article","created":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T10:02:52Z","timestamp":1592992972000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn\u2019s Disease in Japanese Populations"],"prefix":"10.1038","volume":"10","author":[{"given":"Yoichi","family":"Kakuta","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Ichikawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuta","family":"Fuyuno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Hirano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junji","family":"Umeno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takehiro","family":"Torisu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiro","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Asakura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeru","family":"Nakano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Izumiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daisuke","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeo","family":"Naito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rintaro","family":"Moroi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masatake","family":"Kuroha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitake","family":"Kanazawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoya","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hisashi","family":"Shiga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Naito","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Motohiro","family":"Esaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsushi","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minoru","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masao","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshitaka","family":"Kinouchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michiaki","family":"Unno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Atsushi","family":"Masamune","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"66951_CR1","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/nature11582","volume":"491","author":"L Jostins","year":"2012","unstructured":"Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119\u2013124, https:\/\/doi.org\/10.1038\/nature11582 (2012).","journal-title":"Nature"},{"key":"66951_CR2","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/ng.3359","volume":"47","author":"JZ Liu","year":"2015","unstructured":"Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979\u2013986, https:\/\/doi.org\/10.1038\/ng.3359 (2015).","journal-title":"Nat. Genet."},{"key":"66951_CR3","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/nature22969","volume":"547","author":"H Huang","year":"2017","unstructured":"Huang, H. et al. Fine-mapping inflammatory bowel disease loci to single-variant resolution. Nature 547, 173\u2013178, https:\/\/doi.org\/10.1038\/nature22969 (2017).","journal-title":"Nature"},{"key":"66951_CR4","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1093\/ecco-jcc\/jjy197","volume":"13","author":"Y Kakuta","year":"2019","unstructured":"Kakuta, Y. et al. A Genome-wide Association Study Identifying RAP1A as a Novel Susceptibility Gene for Crohn\u2019s Disease in Japanese Individuals. J. Crohns Colitis 13, 648\u2013658, https:\/\/doi.org\/10.1093\/ecco-jcc\/jjy197 (2019).","journal-title":"J. Crohns Colitis"},{"key":"66951_CR5","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1089\/bio.2015.0032","volume":"13","author":"LJ Carithers","year":"2015","unstructured":"Carithers, L. J. et al. A Novel Approach to High-Quality Postmortem Tissue Procurement: The GTEx Project. Biopreserv Biobank 13, 311\u2013319, https:\/\/doi.org\/10.1089\/bio.2015.0032 (2015).","journal-title":"Biopreserv Biobank"},{"key":"66951_CR6","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1038\/ng.3506","volume":"48","author":"A Gusev","year":"2016","unstructured":"Gusev, A. et al. Integrative approaches for large-scale transcriptome-wide association studies. Nat Genet 48, 245\u2013252, https:\/\/doi.org\/10.1038\/ng.3506 (2016).","journal-title":"Nat Genet"},{"key":"66951_CR7","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1016\/S0923-2494(94)80198-3","volume":"145","author":"F Powrie","year":"1994","unstructured":"Powrie, F., Coffman, R. L. & Correa-Oliveira, R. Transfer of CD4+ T cells to C.B-17 SCID mice: a model to study Th1 and Th2 cell differentiation and regulation in vivo. Res Immunol 145, 347\u2013353 (1994).","journal-title":"Res Immunol"},{"key":"66951_CR8","doi-asserted-by":"publisher","first-page":"707","DOI":"10.1042\/CS20100027","volume":"118","author":"G Monteleone","year":"2010","unstructured":"Monteleone, G. & Caprioli, F. T-cell-directed therapies in inflammatory bowel diseases. Clin Sci (Lond) 118, 707\u2013715, https:\/\/doi.org\/10.1042\/CS20100027 (2010).","journal-title":"Clin Sci (Lond)"},{"key":"66951_CR9","doi-asserted-by":"publisher","first-page":"697","DOI":"10.1093\/ecco-jcc\/jjv110","volume":"9","author":"G Fiorino","year":"2015","unstructured":"Fiorino, G. & Omodei, P. D. Psoriasis and Inflammatory Bowel Disease: Two Sides of the Same Coin? J Crohns Colitis 9, 697\u2013698, https:\/\/doi.org\/10.1093\/ecco-jcc\/jjv110 (2015).","journal-title":"J Crohns Colitis"},{"key":"66951_CR10","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1177\/1352458517691620","volume":"24","author":"A Sonnenberg","year":"2018","unstructured":"Sonnenberg, A. & Ajdacic-Gross, V. Similar birth-cohort patterns in Crohn\u2019s disease and multiple sclerosis. Mult Scler 24, 140\u2013149, https:\/\/doi.org\/10.1177\/1352458517691620 (2018).","journal-title":"Mult Scler"},{"key":"66951_CR11","doi-asserted-by":"publisher","first-page":"1935","DOI":"10.1097\/MIB.0000000000000445","volume":"21","author":"P Townsend","year":"2015","unstructured":"Townsend, P. et al. Serum Proteome Profiles in Stricturing Crohn\u2019s Disease: A Pilot Study. Inflamm Bowel Dis 21, 1935\u20131941, https:\/\/doi.org\/10.1097\/MIB.0000000000000445 (2015).","journal-title":"Inflamm Bowel Dis"},{"key":"66951_CR12","doi-asserted-by":"publisher","first-page":"4868","DOI":"10.4049\/jimmunol.171.9.4868","volume":"171","author":"G Bamias","year":"2003","unstructured":"Bamias, G. et al. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J Immunol 171, 4868\u20134874, https:\/\/doi.org\/10.4049\/jimmunol.171.9.4868 (2003).","journal-title":"J Immunol"},{"key":"66951_CR13","doi-asserted-by":"publisher","first-page":"552","DOI":"10.1053\/j.gastro.2008.04.037","volume":"135","author":"H Takedatsu","year":"2008","unstructured":"Takedatsu, H. et al. TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology 135, 552\u2013567, https:\/\/doi.org\/10.1053\/j.gastro.2008.04.037 (2008).","journal-title":"Gastroenterology"},{"key":"66951_CR14","doi-asserted-by":"publisher","first-page":"1089","DOI":"10.1093\/hmg\/ddp005","volume":"18","author":"Y Kakuta","year":"2009","unstructured":"Kakuta, Y. et al. TNFSF15 transcripts from risk haplotype for Crohn\u2019s disease are overexpressed in stimulated T cells. Hum Mol Genet 18, 1089\u20131098, https:\/\/doi.org\/10.1093\/hmg\/ddp005 (2009).","journal-title":"Hum Mol Genet"},{"key":"66951_CR15","doi-asserted-by":"publisher","first-page":"e4719","DOI":"10.1371\/journal.pone.0004719","volume":"4","author":"KS Michelsen","year":"2009","unstructured":"Michelsen, K. S. et al. IBD-associated TL1A gene (TNFSF15) haplotypes determine increased expression of TL1A protein. PLoS One 4, e4719, https:\/\/doi.org\/10.1371\/journal.pone.0004719 (2009).","journal-title":"PLoS One"},{"key":"66951_CR16","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1136\/gut.2006.100297","volume":"55","author":"Y Kakuta","year":"2006","unstructured":"Kakuta, Y., Kinouchi, Y., Negoro, K., Takahashi, S. & Shimosegawa, T. Association study of TNFSF15 polymorphisms in Japanese patients with inflammatory bowel disease. Gut 55, 1527\u20131528, https:\/\/doi.org\/10.1136\/gut.2006.100297 (2006).","journal-title":"Gut"},{"key":"66951_CR17","doi-asserted-by":"publisher","first-page":"3499","DOI":"10.1093\/hmg\/ddi379","volume":"14","author":"K Yamazaki","year":"2005","unstructured":"Yamazaki, K. et al. Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn\u2019s disease. Hum Mol Genet 14, 3499\u20133506, https:\/\/doi.org\/10.1093\/hmg\/ddi379 (2005).","journal-title":"Hum Mol Genet"},{"key":"66951_CR18","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-40941-8","volume":"9","author":"M Niocel","year":"2019","unstructured":"Niocel, M., Appourchaux, R., Nguyen, X. N., Delpeuch, M. & Cimarelli, A. The DNA damage induced by the Cytosine Deaminase APOBEC3A Leads to the production of ROS. Sci Rep 9, 4714, https:\/\/doi.org\/10.1038\/s41598-019-40941-8 (2019).","journal-title":"Sci Rep"},{"key":"66951_CR19","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1002\/humu.22683","volume":"35","author":"S Metsu","year":"2014","unstructured":"Metsu, S. et al. A CGG-repeat expansion mutation in ZNF713 causes FRA7A: association with autistic spectrum disorder in two families. Human mutation 35, 1295\u20131300, https:\/\/doi.org\/10.1002\/humu.22683 (2014).","journal-title":"Human mutation"},{"key":"66951_CR20","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/ng1954","volume":"39","author":"J Hampe","year":"2007","unstructured":"Hampe, J. et al. A genome-wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet 39, 207\u2013211, https:\/\/doi.org\/10.1038\/ng1954 (2007).","journal-title":"Nat Genet"},{"key":"66951_CR21","doi-asserted-by":"publisher","unstructured":"Kakuta, Y. et al. Rare Variants of <em>TNFSF15<\/em> Are Significantly Associated With Crohn\u2019s Disease in Non-Jewish Caucasian Independent of the Known Common Susceptibility SNPs. Gastroenterology 144, S\u2013466, https:\/\/doi.org\/10.1016\/S0016-5085(13)61723-0 (2013).","DOI":"10.1016\/S0016-5085(13)61723-0"},{"key":"66951_CR22","doi-asserted-by":"publisher","first-page":"493","DOI":"10.2188\/jea.JE20150268","volume":"26","author":"S Kuriyama","year":"2016","unstructured":"Kuriyama, S. et al. The Tohoku Medical Megabank Project: Design and Mission. J Epidemiol 26, 493\u2013511, https:\/\/doi.org\/10.2188\/jea.JE20150268 (2016).","journal-title":"J Epidemiol"},{"key":"66951_CR23","unstructured":"Matsui T.H. F., Hisabe T. Proposed diagnostic criteria for Crohn\u2019s disease. Annual reports of the research group of intractable inflammatory bowel disease granted by the Minitry of Health, Labour, and Welfare of Japan., 52\u201354 (2011)."},{"key":"66951_CR24","doi-asserted-by":"publisher","DOI":"10.1186\/s40413-015-0055-2","volume":"8","author":"A Fiocchi","year":"2015","unstructured":"Fiocchi, A. et al. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics. World Allergy Organ J 8, 4, https:\/\/doi.org\/10.1186\/s40413-015-0055-2 (2015).","journal-title":"World Allergy Organ J"},{"key":"66951_CR25","doi-asserted-by":"publisher","unstructured":"Fiocchi, C. & Youngman, K. R. Isolation of human intestinal mucosal mononuclear cells. Curr Protoc Immunol Chapter 7, Unit 7 30, https:\/\/doi.org\/10.1002\/0471142735.im0730s19 (2001).","DOI":"10.1002\/0471142735.im0730s19"},{"key":"66951_CR26","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/jhg.2015.68","volume":"60","author":"Y Kawai","year":"2015","unstructured":"Kawai, Y. et al. Japonica array: improved genotype imputation by designing a population-specific SNP array with 1070 Japanese individuals. J Hum Genet 60, 581\u2013587, https:\/\/doi.org\/10.1038\/jhg.2015.68 (2015).","journal-title":"J Hum Genet"},{"key":"66951_CR27","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9018","volume":"6","author":"M Nagasaki","year":"2015","unstructured":"Nagasaki, M. et al. Rare variant discovery by deep whole-genome sequencing of 1,070 Japanese individuals. Nat Commun 6, 8018, https:\/\/doi.org\/10.1038\/ncomms9018 (2015).","journal-title":"Nat Commun"},{"key":"66951_CR28","doi-asserted-by":"publisher","first-page":"15050","DOI":"10.1038\/hgv.2015.50","volume":"2","author":"Y Yamaguchi-Kabata","year":"2015","unstructured":"Yamaguchi-Kabata, Y. et al. iJGVD: an integrative Japanese genome variation database based on whole-genome sequencing. Human genome variation 2, 15050, https:\/\/doi.org\/10.1038\/hgv.2015.50 (2015).","journal-title":"Human genome variation"},{"key":"66951_CR29","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","volume":"29","author":"A Dobin","year":"2013","unstructured":"Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15\u201321, https:\/\/doi.org\/10.1093\/bioinformatics\/bts635 (2013).","journal-title":"Bioinformatics"},{"key":"66951_CR30","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","volume":"30","author":"Y Liao","year":"2014","unstructured":"Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923\u2013930, https:\/\/doi.org\/10.1093\/bioinformatics\/btt656 (2014).","journal-title":"Bioinformatics"},{"key":"66951_CR31","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","volume":"26","author":"MD Robinson","year":"2010","unstructured":"Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139\u2013140, https:\/\/doi.org\/10.1093\/bioinformatics\/btp616 (2010).","journal-title":"Bioinformatics"},{"key":"66951_CR32","doi-asserted-by":"publisher","first-page":"1479","DOI":"10.1093\/bioinformatics\/btv722","volume":"32","author":"H Ongen","year":"2016","unstructured":"Ongen, H., Buil, A., Brown, A. A., Dermitzakis, E. T. & Delaneau, O. Fast and efficient QTL mapper for thousands of molecular phenotypes. Bioinformatics 32, 1479\u20131485, https:\/\/doi.org\/10.1093\/bioinformatics\/btv722 (2016).","journal-title":"Bioinformatics"},{"key":"66951_CR33","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","volume":"88","author":"J Yang","year":"2011","unstructured":"Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet 88, 76\u201382, https:\/\/doi.org\/10.1016\/j.ajhg.2010.11.011 (2011).","journal-title":"Am J Hum Genet"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-66951-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-66951-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-66951-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T12:21:05Z","timestamp":1670329265000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-66951-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,24]]},"references-count":33,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["66951"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-66951-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,24]]},"assertion":[{"value":"12 September 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 June 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 June 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"10236"}}