The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A

Jayaram Vijayakrishnan, Marc Henrion, Anthony V. Moorman, Bettina Fiege, Rajiv Kumar, Miguel Inacio Da Silva Filho, Amy Holroyd, Rolf Koehler, Hauke Thomsen, Julie A. Irving, James M. Allan, Tracy Lightfoot, Eve Roman, Sally E. Kinsey, Eamonn Sheridan, Pamela D. Thompson, Per Hoffmann, Markus M. Nöthen, Thomas W. Mühleisen, Lewin EiseleClaus R. Bartram, Martin Schrappe, Mel Greaves, Kari Hemminki, Christine J. Harrison, Martin Stanulla, Richard S. Houlston

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16 Scopus citations


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 CDKN2A p.Ala148Thr variant (rs3731249; Odds ratio= 2.42, P= 3.45× 10 '19). 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 CDKN2A transcript suggesting the functional effect of p.Ala148Thr on ALL risk may be through compromised ability to inhibit cyclin D within the cytoplasm.

Original languageEnglish (US)
Article number15065
JournalScientific reports
StatePublished - Oct 14 2015
Externally publishedYes

ASJC Scopus subject areas

  • General


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