{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:00:10Z","timestamp":1788667210816,"version":"build-2803163510"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,6]],"date-time":"2017-06-06T00:00:00Z","timestamp":1496707200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,6]],"date-time":"2017-06-06T00:00:00Z","timestamp":1496707200000},"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>\n                  <jats:p>\n                    Numerous genome-wide association studies (GWAS) have been performed to identify susceptibility genes to various human complex diseases. However, in many cases, neither a functional variant nor a disease susceptibility gene have been clarified. Here, we show an efficient approach for identification of a functional variant in a primary biliary cholangitis (PBC)-susceptible region, chromosome 17q12-21 (\n                    <jats:italic>ORMDL3<\/jats:italic>\n                    -\n                    <jats:italic>GSDMB<\/jats:italic>\n                    -\n                    <jats:italic>ZPBP2<\/jats:italic>\n                    -\n                    <jats:italic>IKZF3<\/jats:italic>\n                    ). High-density association mapping was carried out based on SNP imputation analysis by using the whole-genome sequence data from a reference panel of 1,070 Japanese individuals (1KJPN), together with genotype data from our previous GWAS (PBC patients: n\u2009=\u20091,389; healthy controls: n\u2009=\u20091,508). Among 23 single nucleotide polymorphisms (SNPs) with\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20091.0\u2009\u00d7\u200910\n                    <jats:sup>\u22128<\/jats:sup>\n                    , rs12946510 was identified as the functional variant that influences gene expression via alteration of Forkhead box protein O1 (FOXO1) binding affinity\n                    <jats:italic>in vitro<\/jats:italic>\n                    . Moreover, expression-quantitative trait locus (e-QTL) analyses showed that the PBC susceptibility allele of rs12946510 was significantly associated with lower endogenous expression of\n                    <jats:italic>ORMDL3<\/jats:italic>\n                    and\n                    <jats:italic>GSDMB<\/jats:italic>\n                    in whole blood and spleen. This study not only identified the functional variant in chr.17q12-21 and its molecular mechanism through which it conferred susceptibility to PBC, but it also illustrated an efficient systematic approach for post-GWAS analysis that is applicable to other complex diseases.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-03067-3","type":"journal-article","created":{"date-parts":[[2017,5,31]],"date-time":"2017-05-31T09:29:57Z","timestamp":1496222997000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Identification of the functional variant driving ORMDL3 and GSDMB expression in human chromosome 17q12-21 in primary biliary cholangitis"],"prefix":"10.1038","volume":"7","author":[{"given":"Yuki","family":"Hitomi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaname","family":"Kojima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minae","family":"Kawashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Kawai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nao","family":"Nishida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Aiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michio","family":"Yasunami","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masao","family":"Nagasaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsushi","family":"Tokunaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,6]]},"reference":[{"key":"3067_CR1","doi-asserted-by":"publisher","first-page":"D1001","DOI":"10.1093\/nar\/gkt1229","volume":"42","author":"D Welter","year":"2014","unstructured":"Welter, D. et al. The NHGRI GWAS Catalog, a curated resource of SNP-trait associations. Nucleic Acids Res. \n                           42, D1001\u2013D1006 (2014).","journal-title":"Nucleic Acids Res."},{"key":"3067_CR2","doi-asserted-by":"publisher","first-page":"747","DOI":"10.1038\/nature08494","volume":"461","author":"TA Manolio","year":"2009","unstructured":"Manolio, T. A. et al. Finding the missing heritability of complex diseases. Nature \n                           461, 747\u2013753 (2009).","journal-title":"Nature"},{"key":"3067_CR3","doi-asserted-by":"publisher","first-page":"1114","DOI":"10.1038\/ng.3390","volume":"47","author":"J Yang","year":"2015","unstructured":"Yang, J. et al. Genetic variance estimation with imputed variants finds negligible missing heritability for human height and body mass index. Nat. Genet. \n                           47, 1114\u20131120 (2015).","journal-title":"Nat. Genet."},{"key":"3067_CR4","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1056\/NEJMra043898","volume":"353","author":"MM Kaplan","year":"2005","unstructured":"Kaplan, M. M. & Gershwin, M. E. Primary biliary cholangitis. N. Engl. J. Med. \n                           353, 1261\u20131273 (2005).","journal-title":"N. Engl. J. Med."},{"key":"3067_CR5","doi-asserted-by":"publisher","first-page":"402","DOI":"10.1016\/S0168-8278(99)80097-X","volume":"30","author":"DE Jones","year":"1999","unstructured":"Jones, D. E., Watt, F. E., Metcalf, J. V., Bassendine, M. F. & James, O. F. Familial primary biliary cholangitis reassessed: a geographicallybased population study. J. Hepatol. \n                           30, 402\u2013407 (1999).","journal-title":"J. Hepatol."},{"key":"3067_CR6","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1053\/j.gastro.2004.05.005","volume":"127","author":"C Selmi","year":"2004","unstructured":"Selmi, C. et al. Primary biliary cholangitis in monozygotic and dizygotic twins: genetics, epigenetics, and environment. Gastroenterology \n                           127, 485\u2013492 (2004).","journal-title":"Gastroenterology"},{"key":"3067_CR7","doi-asserted-by":"publisher","first-page":"2544","DOI":"10.1056\/NEJMoa0810440","volume":"360","author":"GM Hirschfield","year":"2009","unstructured":"Hirschfield, G. M. et al. Primary biliary cholangitis associated with HLA, IL12A, and IL12RB2 variants. N. Engl. J. Med. \n                           360, 2544\u20132555 (2009).","journal-title":"N. Engl. J. Med."},{"key":"3067_CR8","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1038\/ng.631","volume":"42","author":"GM Hirschfield","year":"2010","unstructured":"Hirschfield, G. M. et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cholangitis. Nat. Genet. \n                           42, 655\u2013657 (2010).","journal-title":"Nat. Genet."},{"key":"3067_CR9","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1038\/ng.627","volume":"42","author":"X Liu","year":"2010","unstructured":"Liu, X. et al. Genome-wide meta-analyses identify three loci associated with primary biliary cholangitis. Nat. Genet. \n                           42, 658\u2013660 (2010).","journal-title":"Nat. Genet."},{"key":"3067_CR10","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1038\/ng.789","volume":"43","author":"GF Mells","year":"2011","unstructured":"Mells, G. F. et al. Genome-wide association study identifies 12 new susceptibility loci for primary biliary cholangitis. Nat. Genet. \n                           43, 329\u2013332 (2011).","journal-title":"Nat. Genet."},{"key":"3067_CR11","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1038\/gene.2011.89","volume":"13","author":"GM Hirschfield","year":"2012","unstructured":"Hirschfield, G. M. et al. Association of primary biliary cholangitis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. Genes Immun. \n                           13, 328\u2013335 (2012).","journal-title":"Genes Immun."},{"key":"3067_CR12","doi-asserted-by":"publisher","first-page":"1137","DOI":"10.1038\/ng.2395","volume":"44","author":"JZ Liu","year":"2012","unstructured":"Liu, J. Z. et al. Dense fine-mapping study identifies new susceptibility loci for primary biliary cholangitis. Nat. Genet. \n                           44, 1137\u20131141 (2012).","journal-title":"Nat. Genet."},{"key":"3067_CR13","doi-asserted-by":"publisher","first-page":"5209","DOI":"10.1093\/hmg\/dds359","volume":"21","author":"BD Juran","year":"2012","unstructured":"Juran, B. D. et al. Immunochip analyses identify a novel risk locus for primary biliary cirryosis at 13q14, multiple independent associations at four established risk loci and epistasis between 1p31 and 7q32 risk variants. Hum. Mol. Genet. \n                           21, 5209\u20135221 (2012).","journal-title":"Hum. Mol. Genet."},{"key":"3067_CR14","doi-asserted-by":"publisher","first-page":"8019","DOI":"10.1038\/ncomms9019","volume":"6","author":"HJ Cordell","year":"2015","unstructured":"Cordell, H. J. et al. International genome-wide meta-analysis identifies new primary biliary cholangitis risk loci and targetable pathogenic pathways. Nat. Commun. \n                           6, 8019 (2015).","journal-title":"Nat. Commun."},{"key":"3067_CR15","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1016\/j.ajhg.2012.08.010","volume":"91","author":"M Nakamura","year":"2012","unstructured":"Nakamura, M. et al. Genome-wide association study identified TNFSF15 and POU2AF1 as susceptibility locus for primary biliary cholangitis in the Japanese population. Am. J. Hum. Genet. \n                           91, 721\u2013728 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"3067_CR16","unstructured":"Kawashima, M. et al. Genome-wide association study identified PRKCB as a genetic susceptibility locus for primary biliary cholangitis in a Japanese population. Hum. Mol. Genet. 26, 650\u2013659 (2017)."},{"key":"3067_CR17","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1038\/nature06014","volume":"448","author":"MF Moffatt","year":"2007","unstructured":"Moffatt, M. F. et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature. \n                           448, 470\u2013473 (2007).","journal-title":"Nature."},{"key":"3067_CR18","doi-asserted-by":"publisher","first-page":"1211","DOI":"10.1056\/NEJMoa0906312","volume":"363","author":"MF Moffatt","year":"2010","unstructured":"Moffatt, M. F. et al. A large-scale, consortium-based genomewide association study of asthma. N. Engl. J. Med. \n                           363, 1211\u20131221 (2010).","journal-title":"N. Engl. J. Med."},{"key":"3067_CR19","doi-asserted-by":"publisher","first-page":"524","DOI":"10.1016\/j.ajhg.2012.01.010","volume":"90","author":"FA Kurreeman","year":"2012","unstructured":"Kurreeman, F. A. et al. Use of a multiethnic approach to identify rheumatoid- arthritis-susceptibility locus, 1p36 and 17q12. Am. J. Hum. Genet. \n                           90, 524\u2013532 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"3067_CR20","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1016\/j.ajhg.2012.02.023","volume":"90","author":"CJ Lessard","year":"2012","unstructured":"Lessard, C. J. et al. Identification of IRF8, TMEM39A, and IKZF3-ZPBP2 as susceptibility locus for systemic lupus erythematosus in a large-scale multiracial replication study. Am. J. Hum. Genet. \n                           90, 648\u2013660 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"3067_CR21","doi-asserted-by":"publisher","first-page":"955","DOI":"10.1038\/ng.175","volume":"40","author":"JC Barrett","year":"2008","unstructured":"Barrett, J. C. et al. Genome-wide association defines more than 30 distinct susceptibility locus for Crohn\u2019s disease. Nat. Genet. \n                           40, 955\u2013962 (2008).","journal-title":"Nat. Genet."},{"key":"3067_CR22","doi-asserted-by":"publisher","first-page":"332","DOI":"10.1038\/ng.549","volume":"42","author":"DP McGovern","year":"2010","unstructured":"McGovern, D. P. et al. Genome-wide association identifies multiple ulcerative colitis susceptibility locus. Nat. Genet. \n                           42, 332\u2013337 (2010).","journal-title":"Nat. Genet."},{"key":"3067_CR23","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1084\/jem.20031571","volume":"199","author":"M Cortes","year":"2004","unstructured":"Cortes, M. & Georgopoulos, K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J. Exp. Med. \n                           199, 209\u2013219 (2004).","journal-title":"J. Exp. Med."},{"key":"3067_CR24","doi-asserted-by":"publisher","first-page":"1048","DOI":"10.1038\/nature08787","volume":"463","author":"DK Breslow","year":"2010","unstructured":"Breslow, D. K. et al. Orm family proteins mediate sphingolipid homeostasis. Nature \n                           463, 1048\u20131053 (2010).","journal-title":"Nature"},{"key":"3067_CR25","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1093\/hmg\/ddp471","volume":"19","author":"G Cantero-Recasens","year":"2010","unstructured":"Cantero-Recasens, G., Fandos, C., Rubio-Moscardo, F., Valverde, M. A. & Vicente, R. The asthma-associated ORMDL3 gene product regulates endoplasmic reticulum-mediated calcium signaling and cellular stress. Hum. Mol. Genet. \n                           19, 111\u2013121 (2010).","journal-title":"Hum. Mol. Genet."},{"key":"3067_CR26","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1093\/hmg\/dds450","volume":"22","author":"A Carreras-Sureda","year":"2013","unstructured":"Carreras-Sureda, A. et al. ORMDL3 modulates store-operated calcium entry and lymphocyte activation. Hum. Mol. Genet. \n                           22, 519\u2013530 (2013).","journal-title":"Hum. Mol. Genet."},{"key":"3067_CR27","doi-asserted-by":"publisher","first-page":"8018","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. \n                           6, 8018 (2015).","journal-title":"Nat. Commun."},{"key":"3067_CR28","doi-asserted-by":"publisher","first-page":"1790","DOI":"10.1101\/gr.137323.112","volume":"22","author":"AP Boyle","year":"2012","unstructured":"Boyle, A. P. et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. \n                           22, 1790\u20131797 (2012).","journal-title":"Genome Res."},{"key":"3067_CR29","doi-asserted-by":"publisher","first-page":"996","DOI":"10.1101\/gr.229102","volume":"12","author":"WJ Kent","year":"2002","unstructured":"Kent, W. J. et al. The human genome browser at UCSC. Genome Res. \n                           12, 996\u20131006 (2002).","journal-title":"Genome Res."},{"key":"3067_CR30","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1093\/nar\/24.1.238","volume":"24","author":"E Wingender","year":"1996","unstructured":"Wingender, E., Dietze, P., Karas, H. & Kn\u00fcppel, R. TRANSFAC: a database on transcription factors and their DNA binding sites. Nucleic Acids Res. \n                           24, 238\u2013241 (1996).","journal-title":"Nucleic Acids Res."},{"key":"3067_CR31","doi-asserted-by":"crossref","unstructured":"GTEx Consortium. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580\u2013585 (2013).","DOI":"10.1038\/ng.2653"},{"key":"3067_CR32","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1126\/science.1181369","volume":"326","author":"E Lieberman-Aiden","year":"2009","unstructured":"Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science \n                           326, 289\u2013293 (2009).","journal-title":"Science"},{"key":"3067_CR33","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1146\/annurev.genom.9.081307.164242","volume":"10","author":"Y Li","year":"2009","unstructured":"Li, Y., Willer, C., Sanna, S. & Abecasis, G. Genotype imputation. Annu. Rev. Genomics Hum. Genet. \n                           10, 387\u2013406 (2009).","journal-title":"Annu. Rev. Genomics Hum. Genet."},{"key":"3067_CR34","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1534\/g3.111.001198","volume":"1","author":"B Howie","year":"2011","unstructured":"Howie, B., Marchini, J. & Stephens, M. Genotype imputation with thousands of genomes. G3 (Bethesda) \n                           1, 457\u2013470 (2011).","journal-title":"G3 (Bethesda)"},{"key":"3067_CR35","doi-asserted-by":"crossref","unstructured":"1000 Genomes Project Consortium, et al. A global reference for human genetic variation. Nature \n                           526, 68\u201374 (2015).","DOI":"10.1038\/nature15393"},{"key":"3067_CR36","doi-asserted-by":"publisher","first-page":"e114485","DOI":"10.1371\/journal.pone.0114485","volume":"9","author":"Y Li","year":"2014","unstructured":"Li, Y. et al. CRISPR reveals a distal super-enhancer required for Sox2 expression in mouse embryonic stem cells. PLoS One \n                           9, e114485 (2014).","journal-title":"PLoS One"},{"key":"3067_CR37","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/j.jaci.2012.04.041","volume":"130","author":"X Li","year":"2012","unstructured":"Li, X. et al. Genome-wide association studies of asthma indicate opposite immunopathogenesis direction from autoimmune diseases. J. Allergy Clin. Immunol. \n                           130, 861\u2013868 (2012).","journal-title":"J. Allergy Clin. Immunol."},{"key":"3067_CR38","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.jaci.2015.03.014","volume":"136","author":"M Schedel","year":"2015","unstructured":"Schedel, M. et al. Polymorphisms related to ORMDL3 are associated with asthma susceptibility, alterations in transcriptional regulation of ORMDL3, and changes in TH2 cytokine levels. J. Allergy Clin. Immunol. \n                           136, 893\u2013903 (2015).","journal-title":"J. Allergy Clin. Immunol."},{"key":"3067_CR39","doi-asserted-by":"publisher","first-page":"1944","DOI":"10.1002\/hep.26979","volume":"59","author":"CY Yang","year":"2014","unstructured":"Yang, C. Y. et al. IL-12\/Th1 and IL-23\/Th17 biliary microenvironment in primary biliary cholangitis: implications for therapy. Hepatology \n                           59, 1944\u20131953 (2014).","journal-title":"Hepatology"},{"key":"3067_CR40","doi-asserted-by":"publisher","first-page":"737","DOI":"10.1007\/s00439-015-1556-3","volume":"134","author":"Y Hitomi","year":"2015","unstructured":"Hitomi, Y. et al. Human primary biliary cholangitis-susceptible allele of rs4979462 enhances TNFSF15 expression by binding NF-1. Hum. Genet. \n                           134, 737\u2013747 (2015).","journal-title":"Hum. Genet."},{"key":"3067_CR41","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1038\/nmeth.2307","volume":"10","author":"O Delaneau","year":"2013","unstructured":"Delaneau, O., Zagury, J. F. & Marchini, J. Improved whole-chromosome phasing for 50 disease and population genetic studies. Nat. Methods. \n                           10, 5\u20136 (2013).","journal-title":"Nat. Methods."},{"key":"3067_CR42","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1371\/journal.pgen.1000529","volume":"5","author":"BN Howie","year":"2009","unstructured":"Howie, B. N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. \n                           5, 6 (2009).","journal-title":"PLoS Genet."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03067-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03067-3","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03067-3.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:01:26Z","timestamp":1671753686000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03067-3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,6]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["3067"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-03067-3","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,6]]},"assertion":[{"value":"8 February 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"2904"}}