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

Jayaram Vijayakrishnan, Marc Henrion, Anthony 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 Eisele & 7 others Claus R. Bartram, Martin Schrappe, Mel Greaves, Kari Hemminki, Christine J. Harrison, Martin Stanulla, Richard S. Houlston

Research output: Contribution to journalArticle

Abstract

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
Volume5
DOIs
StatePublished - Oct 14 2015
Externally publishedYes

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Single Nucleotide Polymorphism
Genome-Wide Association Study
Cyclin D
Causality
Cytoplasm
B-Lymphocytes
Odds Ratio
Genotype

ASJC Scopus subject areas

  • General

Cite this

Vijayakrishnan, J., Henrion, M., Moorman, A., Fiege, B., Kumar, R., Inacio Da Silva Filho, M., ... Houlston, R. S. (2015). The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. Scientific Reports, 5, [15065]. https://doi.org/10.1038/srep15065

The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. / Vijayakrishnan, Jayaram; Henrion, Marc; Moorman, Anthony; Fiege, Bettina; Kumar, Rajiv; Inacio Da Silva Filho, Miguel; Holroyd, Amy; Koehler, Rolf; Thomsen, Hauke; Irving, Julie A.; Allan, James M.; Lightfoot, Tracy; Roman, Eve; Kinsey, Sally E.; Sheridan, Eamonn; Thompson, Pamela D.; Hoffmann, Per; Nöthen, Markus M.; Mühleisen, Thomas W.; Eisele, Lewin; Bartram, Claus R.; Schrappe, Martin; Greaves, Mel; Hemminki, Kari; Harrison, Christine J.; Stanulla, Martin; Houlston, Richard S.

In: Scientific Reports, Vol. 5, 15065, 14.10.2015.

Research output: Contribution to journalArticle

Vijayakrishnan, J, Henrion, M, Moorman, A, Fiege, B, Kumar, R, Inacio Da Silva Filho, M, Holroyd, A, Koehler, R, Thomsen, H, Irving, JA, Allan, JM, Lightfoot, T, Roman, E, Kinsey, SE, Sheridan, E, Thompson, PD, Hoffmann, P, Nöthen, MM, Mühleisen, TW, Eisele, L, Bartram, CR, Schrappe, M, Greaves, M, Hemminki, K, Harrison, CJ, Stanulla, M & Houlston, RS 2015, 'The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A', Scientific Reports, vol. 5, 15065. https://doi.org/10.1038/srep15065
Vijayakrishnan, Jayaram ; Henrion, Marc ; Moorman, Anthony ; Fiege, Bettina ; Kumar, Rajiv ; Inacio Da Silva Filho, Miguel ; Holroyd, Amy ; Koehler, Rolf ; Thomsen, Hauke ; Irving, Julie A. ; Allan, James M. ; Lightfoot, Tracy ; Roman, Eve ; Kinsey, Sally E. ; Sheridan, Eamonn ; Thompson, Pamela D. ; Hoffmann, Per ; Nöthen, Markus M. ; Mühleisen, Thomas W. ; Eisele, Lewin ; Bartram, Claus R. ; Schrappe, Martin ; Greaves, Mel ; Hemminki, Kari ; Harrison, Christine J. ; Stanulla, Martin ; Houlston, Richard S. / The 9p21.3 risk of childhood acute lymphoblastic leukaemia is explained by a rare high-impact variant in CDKN2A. In: Scientific Reports. 2015 ; Vol. 5.
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