A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1.
Genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of childhood acute lymphoblastic leukemia (ALL). To identify new susceptibility loci for the largest subtype of ALL, B-cell precursor ALL (BCP-ALL), we conducted a meta-analysis of two GWASs with imputation using 1000 Genomes and UK10K Project data as reference (totaling 1658 cases and 7224 controls). After genotyping an additional 2525 cases and 3575 controls, we identify new susceptibility loci for BCP-ALL mapping to 10q26.13 (rs35837782, LHPP, P=1.38 × 10-11) and 12q23.1 (rs4762284, ELK3, P=8.41 × 10-9). We also provide confirmatory evidence for the existence of independent risk loci at 9p21.3, but show that the association marked by rs77728904 can be accounted for by linkage disequilibrium with the rare high-impact CDKN2A p.Ala148Thr variant rs3731249. Our data provide further insights into genetic susceptibility to ALL and its biology.
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
J
J
Vijayakrishnan
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
R
R
Kumar
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
M Y R
MY
Henrion
Leukemia Research Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
A V
AV
Moorman
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
P S
PS
Rachakonda
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
I
I
Hosen
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
M I
MI
da Silva Filho
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
A
A
Holroyd
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
S E
SE
Dobbins
Department of Human Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
R
R
Koehler
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
H
H
Thomsen
Leukemia Research Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
J A
JA
Irving
Leukemia Research Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
J M
JM
Allan
Department of Health Sciences, Epidemiology and Cancer Statistics Group, University of York, York, UK.
T
T
Lightfoot
Department of Health Sciences, Epidemiology and Cancer Statistics Group, University of York, York, UK.
E
E
Roman
Department of Paediatric and Adolescent Haematology and Oncology, Leeds General Infirmary, Leeds, UK.
S E
SE
Kinsey
Medical Genetics Research Group, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.
E
E
Sheridan
Paediatric and Familial Cancer Research Group, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Manchester, UK.
P D
PD
Thompson
Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Biomedicine, Human Genomics Research Group, University Hospital Basel, Basel, Switzerland.
P
P
Hoffmann
Institute of Human Genetics, University of Bonn, Bonn, Germany.
M M
MM
Nöthen
Institute of Human Genetics, University of Bonn, Bonn, Germany.
S
S
Heilmann-Heimbach
Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany.
K H
KH
Jöckel
Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Sutton, UK.
M
M
Greaves
Leukemia Research Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
C J
CJ
Harrison
Department of Human Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
C R
CR
Bartram
General Paediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
M
M
Schrappe
Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany.
M
M
Stanulla
Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
K
K
Hemminki
Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
R S
RS
Houlston
D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D042002:Chromatin Assembly and Disassembly; D002872:Chromosome Deletion; D002879:Chromosomes, Human, Pair 10; D002881:Chromosomes, Human, Pair 12; D019295:Computational Biology / Q000379:methods; D005260:Female; D020869:Gene Expression Profiling; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D058977:Molecular Sequence Annotation; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality; D040641:Quantitative Trait Loci; D017422:Sequence Analysis, DNA
Haematologica. 2013 Jul;98 (7):1081-8
23508010
Cell. 2013 Nov 7;155(4):934-47
24119843
Br J Cancer. 2007 Nov 5;97(9):1305-9
17895893
PLoS Genet. 2006 Dec;2(12):e190
17194218
Nat Genet. 2006 Aug;38(8):904-9
16862161
Stat Med. 2002 Jun 15;21(11):1539-58
12111919
Blood. 2013 Nov 7;122(19):3298-307
23996088
Mol Cell Biol. 1994 May;14(5):3292-309
7909357
Nature. 2015 Oct 1;526(7571):82-90
26367797
PLoS Biol. 2011 Jan 18;9(1):e1000580
21267062
Nat Genet. 2010 Jun;42(6):492-4
20453839
Blood. 2009 Jan 1;113(1):100-7
18838613
Nat Methods. 2011 Dec 04;9(2):179-81
22138821
Nucleic Acids Res. 2012 Jan;40(Database issue):D930-4
22064851
Am J Epidemiol. 2012 Sep 1;176(5):402-8
22899827
Nat Genet. 2009 Sep;41(9):1006-10
19684604
Haematologica. 2011 Jul;96(7):1049-54
21459794
PLoS Genet. 2011 Feb 03;7(2):e1002003
21304890
Nat Genet. 2008 Dec;40(12):1407-9
18978787
Genome Res. 2005 Jul;15(7):901-13
15965027
Sci Rep. 2015 Oct 14;5:15065
26463672
Nat Genet. 2007 Jul;39(7):906-13
17572673
Nature. 2009 Sep 10;461(7261):272-6
19684571
Science. 2002 Jun 21;296(5576):2225-9
12029063
Nature. 2012 Sep 6;489(7414):57-74
22955616
PLoS Biol. 2011 Jan 18;9(1):e1000579
21267061
PLoS Genet. 2007 Jul;3(7):e114
17676998
Lancet Oncol. 2013 Mar;14 (3):199-209
23395119
Leukemia. 2012 Oct;26(10):2212-5
22456626
Nat Commun. 2016 Feb 12;7:10635
26868379
Nat Methods. 2010 Apr;7(4):248-9
20354512
Hum Mol Genet. 2008 Oct 15;17(R2):R122-8
18852200
J Biochem. 2003 May;133(5):607-14
12801912
Leukemia. 2000 Mar;14(3):356-63
10720126
Nat Rev Cancer. 2006 Mar;6(3):193-203
16467884
Br J Haematol. 2012 Dec;159(5):585-8
23025517
Cancer Chemother Rep. 1966 Mar;50(3):163-70
5910392
Genome Res. 2012 Sep;22(9):1790-7
22955989
Nat Genet. 2014 Mar;46(3):310-5
24487276
Nat Genet. 2010 May;42(5):436-40
20418889
Am J Hum Genet. 2007 Sep;81(3):559-75
17701901
Blood. 2010 Apr 22;115(16):3206-14
20154213
Br Med Bull. 1996 Oct;52(4):682-703
9039726
PLoS One. 2014 Sep 10;9(9):e107497
25208325
Nat Commun. 2015 Sep 14;6:8111
26368830
Cancer Res. 2015 Nov 15;75(22):4884-94
26527286
Am J Hum Genet. 2011 Jan 7;88(1):76-82
21167468
Blood Rev. 2012 May;26(3):123-35
22436535
Nat Commun. 2015 Jun 24;6:7553
26104880
PLoS Genet. 2009 Jun;5(6):e1000529
19543373
Nat Genet. 2002 May;31(1):33-6
11984562
Science. 2005 Oct 14;310(5746):321-4
16224025
Nat Genet. 2013 Oct;45(10):1238-43
24013639