{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T16:54:42Z","timestamp":1781196882406,"version":"3.54.1"},"reference-count":29,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2015,10,14]],"date-time":"2015-10-14T00:00:00Z","timestamp":1444780800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,10,14]],"date-time":"2015-10-14T00:00:00Z","timestamp":1444780800000},"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>Genome-wide association studies (GWAS) have provided strong evidence for inherited predisposition to childhood acute lymphoblastic leukaemia (ALL) identifying a number of risk loci. We have previously shown common SNPs at 9p21.3 influence ALL risk. These SNP associations are generally not themselves candidates for causality, but simply act as markers for functional variants. By means of imputation of GWAS data and subsequent validation SNP genotyping totalling 2,177 ALL cases and 8,240 controls, we have shown that the 9p21.3 association can be ascribed to the rare high-impact<jats:italic>CDKN2A<\/jats:italic>p.Ala148Thr variant (rs3731249; Odds ratio\u2009=\u20092.42,<jats:italic>P\u2009<\/jats:italic>=\u20093.45\u2009\u00d7\u200910<jats:sup>\u221219<\/jats:sup>). The association between rs3731249 genotype and risk was not specific to particular subtype of B-cell ALL. The rs3731249 variant is associated with predominant nuclear localisation of the<jats:italic>CDKN2A<\/jats:italic>transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.<\/jats:p>","DOI":"10.1038\/srep15065","type":"journal-article","created":{"date-parts":[[2015,10,14]],"date-time":"2015-10-14T09:22:47Z","timestamp":1444814567000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A"],"prefix":"10.1038","volume":"5","author":[{"given":"Jayaram","family":"Vijayakrishnan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Henrion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony V.","family":"Moorman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Fiege","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Inacio da Silva Filho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Holroyd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rolf","family":"Koehler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hauke","family":"Thomsen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie A.","family":"Irving","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Allan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracy","family":"Lightfoot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eve","family":"Roman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sally E.","family":"Kinsey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eamonn","family":"Sheridan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela D.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Per","family":"Hoffmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus M.","family":"N\u00f6then","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"M\u00fchleisen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lewin","family":"Eisele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus R.","family":"Bartram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Schrappe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mel","family":"Greaves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari","family":"Hemminki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine J.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Stanulla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard S.","family":"Houlston","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,10,14]]},"reference":[{"key":"BFsrep15065_CR1","doi-asserted-by":"publisher","first-page":"682","DOI":"10.1093\/oxfordjournals.bmb.a011577","volume":"52","author":"CA Stiller","year":"1996","unstructured":"Stiller, C. A. & Parkin, D. M. Geographic and ethnic variations in the incidence of childhood cancer. Br Med Bull 52, 682\u2013703 (1996).","journal-title":"Br Med Bull"},{"key":"BFsrep15065_CR2","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/bjh.12069","volume":"159","author":"E Kharazmi","year":"2012","unstructured":"Kharazmi, E. et al. Familial risks for childhood acute lymphocytic leukaemia in Sweden and Finland: far exceeding the effects of known germline variants. Br J Haematol 159, 585\u20138 (2012).","journal-title":"Br J Haematol"},{"key":"BFsrep15065_CR3","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1038\/ng.430","volume":"41","author":"E Papaemmanuil","year":"2009","unstructured":"Papaemmanuil, E. et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nat Genet 41, 1006\u201310 (2009).","journal-title":"Nat Genet"},{"key":"BFsrep15065_CR4","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1038\/sj.bjc.6603997","volume":"97","author":"S Penegar","year":"2007","unstructured":"Penegar, S. et al. National study of colorectal cancer genetics. Br J Cancer 97, 1305\u20139 (2007).","journal-title":"Br J Cancer"},{"key":"BFsrep15065_CR5","doi-asserted-by":"publisher","first-page":"2692","DOI":"10.1016\/j.jmb.2014.04.026","volume":"426","author":"CM Yates","year":"2014","unstructured":"Yates, C. M., Filippis, I., Kelley, L. A. & Sternberg, M. J. SuSPect: enhanced prediction of single amino acid variant (SAV) phenotype using network features. J Mol Biol 426, 2692\u2013701 (2014).","journal-title":"J Mol Biol"},{"key":"BFsrep15065_CR6","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1002\/(SICI)1097-0215(19990719)82:2<305::AID-IJC24>3.0.CO;2-Z","volume":"82","author":"GJ Walker","year":"1999","unstructured":"Walker, G. J., Gabrielli, B. G., Castellano, M. & Hayward, N. K. Functional reassessment of P16 variants using a transfection-based assay. Int J Cancer 82, 305\u201312 (1999).","journal-title":"Int J Cancer"},{"key":"BFsrep15065_CR7","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1182\/blood-2008-07-166801","volume":"113","author":"S Sulong","year":"2009","unstructured":"Sulong, S. et al. A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity and association with specific cytogenetic subgroups. Blood 113, 100\u20137 (2009).","journal-title":"Blood"},{"key":"BFsrep15065_CR8","doi-asserted-by":"publisher","first-page":"1081","DOI":"10.3324\/haematol.2013.085175","volume":"98","author":"CJ Schwab","year":"2013","unstructured":"Schwab, C. J. et al. Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features. Haematologica 98, 1081\u20138 (2013).","journal-title":"Haematologica"},{"key":"BFsrep15065_CR9","doi-asserted-by":"publisher","first-page":"3553","DOI":"10.1182\/blood-2009-10-251413","volume":"115","author":"CM Bateman","year":"2010","unstructured":"Bateman, C. M. et al. Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood 115, 3553\u20138 (2010).","journal-title":"Blood"},{"key":"BFsrep15065_CR10","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1038\/leu.2012.155","volume":"27","author":"S Krentz","year":"2013","unstructured":"Krentz, S. et al. Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia. Leukemia 27, 295\u2013304 (2013).","journal-title":"Leukemia"},{"key":"BFsrep15065_CR11","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1158\/2159-8290.CD-12-0095","volume":"2","author":"E Cerami","year":"2012","unstructured":"Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2, 401\u20134 (2012).","journal-title":"Cancer Discov"},{"key":"BFsrep15065_CR12","doi-asserted-by":"publisher","first-page":"736","DOI":"10.1038\/ng.3002","volume":"46","author":"Y Wang","year":"2014","unstructured":"Wang, Y. et al. Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer. Nat Genet 46, 736\u201341 (2014).","journal-title":"Nat Genet"},{"key":"BFsrep15065_CR13","doi-asserted-by":"publisher","first-page":"4729","DOI":"10.1093\/hmg\/ddu177","volume":"23","author":"N Whiffin","year":"2014","unstructured":"Whiffin, N. et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet 23, 4729\u201337 (2014).","journal-title":"Hum Mol Genet"},{"key":"BFsrep15065_CR14","doi-asserted-by":"publisher","first-page":"1877","DOI":"10.1007\/s00439-012-1212-0","volume":"131","author":"P Rajaraman","year":"2012","unstructured":"Rajaraman, P. et al. Genome-wide association study of glioma and meta-analysis. Hum Genet 131, 1877\u201388 (2012).","journal-title":"Hum Genet"},{"key":"BFsrep15065_CR15","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/ng.2843","volume":"46","author":"HE Speedy","year":"2014","unstructured":"Speedy, H. E. et al. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat Genet 46, 56\u201360 (2014).","journal-title":"Nat Genet"},{"key":"BFsrep15065_CR16","doi-asserted-by":"crossref","unstructured":"The United Kingdom Childhood Cancer Study: objectives, materials and methods. UK Childhood Cancer Study Investigators. Br J Cancer 82, 1073\u2013102 (2000).","DOI":"10.1054\/bjoc.1999.1045"},{"key":"BFsrep15065_CR17","doi-asserted-by":"publisher","first-page":"3298","DOI":"10.1182\/blood-2013-03-491316","volume":"122","author":"G Migliorini","year":"2013","unstructured":"Migliorini, G. et al. Variation at 10p12.2 and 10p14 influences risk of childhood B-cell acute lymphoblastic leukemia and phenotype. Blood 122, 3298\u2013307 (2013).","journal-title":"Blood"},{"key":"BFsrep15065_CR18","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1086\/519795","volume":"81","author":"S Purcell","year":"2007","unstructured":"Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81, 559\u201375 (2007).","journal-title":"Am J Hum Genet"},{"key":"BFsrep15065_CR19","doi-asserted-by":"publisher","first-page":"906","DOI":"10.1038\/ng2088","volume":"39","author":"J Marchini","year":"2007","unstructured":"Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39, 906\u201313 (2007).","journal-title":"Nat Genet"},{"key":"BFsrep15065_CR20","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1038\/ng1653","volume":"37","author":"DG Clayton","year":"2005","unstructured":"Clayton, D. G. et al. Population structure, differential bias and genomic control in a large-scale, case-control association study. Nat Genet 37, 1243\u20136 (2005).","journal-title":"Nat Genet"},{"key":"BFsrep15065_CR21","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/ng1847","volume":"38","author":"AL Price","year":"2006","unstructured":"Price, A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38, 904\u20139 (2006).","journal-title":"Nat Genet"},{"key":"BFsrep15065_CR22","doi-asserted-by":"publisher","first-page":"1539","DOI":"10.1002\/sim.1186","volume":"21","author":"JP Higgins","year":"2002","unstructured":"Higgins, J. P. & Thompson, S. G. Quantifying heterogeneity in a meta-analysis. Stat Med 21, 1539\u201358 (2002).","journal-title":"Stat Med"},{"key":"BFsrep15065_CR23","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","volume":"315","author":"M Egger","year":"1997","unstructured":"Egger, M., Smith, G. D., Schneider, M. & Minder, C. Bias in meta-analysis detected by a simple, graphical test. BMJ 315, 629\u2013634 (1997).","journal-title":"BMJ"},{"key":"BFsrep15065_CR24","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1126\/science.1117196","volume":"310","author":"S Myers","year":"2005","unstructured":"Myers, S., Bottolo, L., Freeman, C., McVean, G. & Donnelly, P. A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321\u20134 (2005).","journal-title":"Science"},{"key":"BFsrep15065_CR25","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1126\/science.1069424","volume":"296","author":"SB Gabriel","year":"2002","unstructured":"Gabriel, S. B. et al. The structure of haplotype blocks in the human genome. Science 296, 2225\u20139 (2002).","journal-title":"Science"},{"key":"BFsrep15065_CR26","doi-asserted-by":"publisher","first-page":"901","DOI":"10.1101\/gr.3577405","volume":"15","author":"GM Cooper","year":"2005","unstructured":"Cooper, G. M. et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15, 901\u201313 (2005).","journal-title":"Genome Res"},{"key":"BFsrep15065_CR27","doi-asserted-by":"publisher","first-page":"1034","DOI":"10.1101\/gr.3715005","volume":"15","author":"A Siepel","year":"2005","unstructured":"Siepel, A. et al. Evolutionarily conserved elements in vertebrate, insect, worm and yeast genomes. Genome Res 15, 1034\u201350 (2005).","journal-title":"Genome Res"},{"key":"BFsrep15065_CR28","doi-asserted-by":"publisher","first-page":"e107497","DOI":"10.1371\/journal.pone.0107497","volume":"9","author":"M Scales","year":"2014","unstructured":"Scales, M., Jager, R., Migliorini, G., Houlston, R. S. & Henrion, M. Y. visPIG--a web tool for producing multi-region, multi-track, multi-scale plots of genetic data. PLoS One 9, e107497 (2014).","journal-title":"PLoS One"},{"key":"BFsrep15065_CR29","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1038\/nature09906","volume":"473","author":"J Ernst","year":"2011","unstructured":"Ernst, J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43\u20139 (2011).","journal-title":"Nature"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep15065.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15065","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep15065.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,11]],"date-time":"2024-06-11T20:06:35Z","timestamp":1718136395000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep15065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,10,14]]},"references-count":29,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2015,12,7]]}},"alternative-id":["BFsrep15065"],"URL":"https:\/\/doi.org\/10.1038\/srep15065","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,10,14]]},"assertion":[{"value":"26 February 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2015","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 October 2015","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"15065"}}