A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1

J Vijayakrishnan; R Kumar; M Y R Henrion; A V Moorman; P S Rachakonda; I Hosen; M I da Silva Filho; A Holroyd; S E Dobbins; R Koehler; H Thomsen; J A Irving; J M Allan; T Lightfoot; E Roman; S E Kinsey; E Sheridan; P D Thompson; P Hoffmann; M M Nöthen; S Heilmann-Heimbach; K H Jöckel; M Greaves; C J Harrison; C R Bartram; M Schrappe; M Stanulla; K Hemminki; R S Houlston

doi:10.1038/leu.2016.271

A genome-wide association study identifies risk loci for childhood acute lymphoblastic leukemia at 10q26.13 and 12q23.1

Leukemia. 2017 Mar;31(3):573-579. doi: 10.1038/leu.2016.271. Epub 2016 Oct 3.

Authors

J Vijayakrishnan¹, R Kumar², M Y R Henrion¹, A V Moorman³, P S Rachakonda², I Hosen², M I da Silva Filho², A Holroyd¹, S E Dobbins¹, R Koehler⁴, H Thomsen², J A Irving³, J M Allan³, T Lightfoot⁵, E Roman⁵, S E Kinsey⁶, E Sheridan⁷, P D Thompson⁸, P Hoffmann^{9

10}, M M Nöthen⁹, S Heilmann-Heimbach⁹, K H Jöckel¹¹, M Greaves¹², C J Harrison³, C R Bartram⁴, M Schrappe¹³, M Stanulla¹⁴, K Hemminki^{2

15}, R S Houlston¹

Affiliations

¹ Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, UK.
² Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
³ Leukemia Research Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
⁴ Department of Human Genetics, Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
⁵ Department of Health Sciences, Epidemiology and Cancer Statistics Group, University of York, York, UK.
⁶ Department of Paediatric and Adolescent Haematology and Oncology, Leeds General Infirmary, Leeds, UK.
⁷ Medical Genetics Research Group, Leeds Institute of Biomedical & Clinical Sciences, University of Leeds, Leeds, UK.
⁸ Paediatric and Familial Cancer Research Group, Institute of Cancer Sciences, University of Manchester, St Mary's Hospital, Manchester, UK.
⁹ Institute of Human Genetics, University of Bonn, Bonn, Germany.
¹⁰ Department of Biomedicine, Human Genomics Research Group, University Hospital Basel, Basel, Switzerland.
¹¹ Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany.
¹² Haemato-Oncology Research Unit, Division of Molecular Pathology, Institute of Cancer Research, Sutton, UK.
¹³ General Paediatrics, University Hospital Schleswig-Holstein, Kiel, Germany.
¹⁴ Department of Paediatric Haematology and Oncology, Hannover Medical School, Hannover, Germany.
¹⁵ Center for Primary Health Care Research, Lund University, Malmö, Sweden.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Child
Child, Preschool
Chromatin Assembly and Disassembly
Chromosome Deletion
Chromosomes, Human, Pair 10*
Chromosomes, Human, Pair 12*
Computational Biology / methods
Female
Gene Expression Profiling
Genetic Loci*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Genotype
High-Throughput Nucleotide Sequencing
Humans
Infant
Male
Molecular Sequence Annotation
Polymorphism, Single Nucleotide
Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
Precursor Cell Lymphoblastic Leukemia-Lymphoma / mortality
Quantitative Trait Loci
Sequence Analysis, DNA

Abstract

Publication types

MeSH terms

Grants and funding