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Germline genomic variants associated with childhood acute lymphoblastic leukemia

Nature Genetics volume 41, pages 1001–1005 (2009)Cite this article

Abstract

Using the Affymetrix 500K Mapping array and publicly available genotypes, we identified 18 SNPs whose allele frequency differed significantly(P < 1 × 10−5) between pediatric acute lymphoblastic leukemia (ALL) cases (n = 317) and non-ALL controls (n = 17,958). Two SNPs in ARID5B not only differed between ALL and non-ALL groups (rs10821936, P = 1.4 × 10−15, odds ratio (OR) = 1.91; rs10994982, P = 5.7 × 10−9, OR = 1.62) but also distinguished B-hyperdiploid ALL from other subtypes (rs10821936, P = 1.62 × 10−5, OR = 2.17; rs10994982, P = 0.003, OR 1.72). These ARID5B SNPs also distinguished B-hyperdiploid ALL from other subtypes in an independent validation cohort (n = 124 children with ALL; P = 0.003 and P = 0.0008, OR 2.45 and 2.86, respectively) and were associated with methotrexate accumulation and gene expression pattern in leukemic lymphoblasts. We conclude that germline variants affect susceptibility to, and characteristics of, specific ALL subtypes.

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Figure 1: Genome-wide P values comparing allele frequency of SNPs between the ALL and combined non-ALL groups according to chromosome.

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Acknowledgements

We thank our protocol co-investigators, clinical and research staff (particularly P. McGill, J. Cai, S.-H. Chen, N. Kornegay and J. Pauley), the Hartwell Center for Bioinformatics and Biotechnology at St. Jude Children's Research Hospital (Memphis, Tennessee), S. Das at the Genetic Services Laboratory at the University of Chicago (Chicago, Illinois) and the study participants and their families who participated. We thank R. Whitson from City of Hope Hospital (Duarte, California) for constructive discussions.

This study makes use of data generated by the Wellcome Trust Case Control Consortium (WTCCC). A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under award 076113.

Funding support for the Genome-Wide Association of Schizophrenia Study was provided by the National Institute of Mental Health (R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The datasets used for the analyses described in this manuscript were obtained from the database of Genotype and Phenotype database (dbGaP) found at http://www.ncbi.nlm.nih.gov/gap through dbGaP (accession number phs000021.v1.p1). Samples and associated phenotype data for the Genome-Wide Association of Schizophrenia Study were provided by the Molecular Genetics of Schizophrenia Collaboration (Principal Investigator: P.V. Gejman, Evanston Northwestern Healthcare (ENH) and Northwestern University, Evanston, Illinois).

Funding support for the Whole Genome Association Study of Bipolar Disorder was provided by the US National Institute of Mental Health (NIMH) and the genotyping of samples was provided through the Genetic Association Information Network (GAIN). The datasets used for the analyses described in this manuscript were obtained from dbGaP (accession number phs000017.v1.p1). Samples and associated phenotype data for the Collaborative Genomic Study of Bipolar Disorder were provided by The NIMH Genetics Initiative for Bipolar Disorder. Data and biomaterials were collected in four projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1991 to 1998, the principal investigators and co-investigators were: Indiana University, Indianapolis, Indiana, U01 MH46282, J. Nurnberger, M. Miller and E. Bowman; Washington University, St. Louis, Missouri, U01 MH46280, T. Reich, A. Goate and J. Rice; Johns Hopkins University, Baltimore, Maryland, U01 MH46274, J.R. DePaulo Jr., S. Simpson and C. Stine; NIMH Intramural Research Program, Clinical Neurogenetics Branch, Bethesda, Maryland, E. Gershon, D. Kazuba and E. Maxwell. Data and biomaterials were collected as part of ten projects that participated in the NIMH Bipolar Disorder Genetics Initiative. From 1999 to 2003, the principal investigators and co-investigators were: Indiana University, Indianapolis, Indiana, R01 MH59545, J. Nurnberger, M.J. Miller, E.S. Bowman, N.L. Rau, P.R. Moe, N. Samavedy, R. El-Mallakh (University of Louisville, Louisville, Kentucky), H. Manji (Wayne State University, Detroit, Michigan), D.A. Glitz (Wayne State University), E.T. Meyer, C. Smiley, T. Foroud, L. Flury, D.M. Dick and H. Edenberg; Washington University, St. Louis, Missouri, R01 MH059534, J. Rice, T. Reich, A. Goate and L. Bierut; Johns Hopkins University, Baltimore, Maryland, R01 MH59533, M. McInnis, J.R. DePaulo Jr., D.F. MacKinnon, F.M. Mondimore, J.B. Potash, P.P. Zandi, D. Avramopoulos and J. Payne; University of Pennsylvania, Philadelphia, Pennsylvania, R01 MH59553, W. Berrettini; University of California, Irvine, California, R01 MH60068, W. Byerley and M. Vawter; University of Iowa, Iowa City, Iowa, R01 MH059548, W. Coryell and R. Crowe; University of Chicago, Chicago, Illinois, R01 MH59535, E. Gershon, J. Badner, F. McMahon, C. Liu, A. Sanders, M. Caserta, S. Dinwiddie, T. Nguyen and D. Harakal; University of California, San Diego, California, R01 MH59567, J. Kelsoe and R. McKinney; Rush University, Chicago, Illinois, R01 MH059556, W. Scheftner, H.M. Kravitz, D. Marta, A. Vaughn-Brown and L. Bederow; NIMH Intramural Research Program, Bethesda, Maryland, 1Z01MH002810-01, F.J. McMahon, L. Kassem, S. Detera-Wadleigh, L. Austin and D.L. Murphy.

This study was supported by the US National Cancer Institute (grants CA 51001, CA 078224, CA 36401 and CA 21765), the National Institute of Health/National Institutes of General Medical Sciences Pharmacogenetics Research Network and Database (U01 GM61393, U01 HL65899, U01GM61374; http://www.pharmgkb.org/), by a Center of Excellence grant from the State of Tennessee and by the American Lebanese Syrian Associated Charities (ALSAC).

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  1. Lisa R Treviño and Wenjian Yang: These authors contributed equally to this work.

Authors and Affiliations

  1. St. Jude Children's Research Hospital, Memphis, Tennessee, USA

    Lisa R Treviño, Wenjian Yang, Deborah French, Geoffrey Neale, James Downing, Susana C Raimondi, Ching-Hon Pui, William E Evans & Mary V Relling

  2. University of Colorado, Denver, Colorado, USA

    Stephen P Hunger

  3. New York University Medical Center, New York, New York, USA

    William L Carroll

  4. University of Florida, Gainesville, Florida, USA

    Meenakshi Devidas

  5. University of New Mexico, Albuquerque, New Mexico, USA

    Cheryl Willman

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  1. Lisa R Treviño
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Contributions

L.R.T., W.Y. and M.V.R designed the study. M.V.R. and W.E.E. directed the study. L.R.T., W.Y., D.F., S.P.H., W.L.C., M.D., C.W., G.N., J.D., S.C.R., C.-H.P, W.E.E. and M.V.R. helped with data analysis and data interpretation. W.Y. conducted the statistical genomic analysis. S.R. performed and guided cytogenetic data analysis. S.H., W.L.C., M.D. and C.-H.P. provided clinical data. J.D. provided leukemic lymphoblast gene expression data.

Corresponding author

Correspondence to Mary V Relling.

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Treviño, L., Yang, W., French, D. et al. Germline genomic variants associated with childhood acute lymphoblastic leukemia. Nat Genet 41, 1001–1005 (2009). https://doi.org/10.1038/ng.432

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