A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3)

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Abstract

To identify susceptibility loci for classical Hodgkin's lymphoma (cHL), we conducted a genome-wide association study of 589 individuals with cHL (cases) and 5,199 controls with validation in four independent samples totaling 2,057 cases and 3,416 controls. We identified three new susceptibility loci at 2p16.1 (rs1432295, REL, odds ratio (OR) = 1.22, combined P = 1.91 × 10−8), 8q24.21 (rs2019960, PVT1, OR = 1.33, combined P = 1.26 × 10−13) and 10p14 (rs501764, GATA3, OR = 1.25, combined P = 7.05 × 10−8). Furthermore, we confirmed the role of the major histocompatibility complex in disease etiology by revealing a strong human leukocyte antigen (HLA) association (rs6903608, OR = 1.70, combined P = 2.84 × 10−50). These data provide new insight into the pathogenesis of cHL.

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Figure 1: Genome-wide association results from the discovery phase.
Figure 2: Regional plots of association results and recombination rates for the 2p16.1, 8q24.21 and 10p14 susceptibility loci.

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Acknowledgements

Leukemia Lymphoma Research (UK) and Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) provided principal funding for the study. We acknowledge National Health Service (NHS) funding to the National Institute for Health Research (NIHR) Biomedical Research Centre. This study made use of control genotyping data generated by the Wellcome Trust Case Control Consortium. We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, which was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. 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 awards 076113 and 085475. At the Institute of Cancer Research, sample and data acquisition was supported by Breakthrough Breast Cancer and the European Union, and we acknowledge NHS funding to the NIHR Biomedical Research Centre. We are grateful to the patients and their clinicians who participated in this collection (Supplementary Note). Work at the Leukaemia Research Fund (LRF) Virus Centre was funded by Leukaemia and Lymphoma Research. Sample and data acquisition for the UK replication series was also supported by the Kay Kendall Leukaemia Fund. The Epidemiology and Genetics Lymphoma Case-Control Study (ELCCS) was funded by Leukaemia and Lymphoma Research. Grant support to the German Study Group was through Deutsche Krebshilfe and the EU, grant HEALTH-F4-2007-200767. The SCALE study is supported by the Lundbeck Foundation grant R19 A2364, the Danish Cancer Research Foundation grant 41-08 and the Danish Cancer Society grant DP 08155. At the Department of Pathology and Medical Biology, University of Groningen, sample and data acquisition was supported by two grants from the Dutch Cancer Society (RUG 200-2315 and RUG 2009-4313). The Netherlands Cancer Institute (NKI) study was supported by the Dutch Cancer Society (grants No. NKI 98-1833, NKI 04-3068, NKI 08-3994) and the EU 6th framework programme (project no. 012926). We thank A. Kesminiene for coordinating the EU-framework project, M. Schaapveld and A. Eggermond for data management and L. Braaf and I. Mikolajewska for lab assistance. We are indebted to the patients and physicians who participated in this collection (Supplementary Note).

Author information

R.S.H. designed the study and obtained financial support. R.S.H. drafted the manuscript with contributions from P.B., V.E.-M., Y.M. and S.E.D. Y.M. and V.E.-M. performed statistical and bioinformatic analyses. P.B. performed sample coordination and laboratory analyses. B.O., Amy Lloyd and J.V. performed genotyping. A.J.S., A.A. and R.C. provided samples and data from a study conducted at the Institute of Cancer Research. E.R. initiated ELCCS. T.L., M.T. and E.R. managed and prepared Epidemiology and Genetics Lymphoma Case-Control Study samples. R.F.J. designed and conducted studies contributing to the UK replication series, and R.F.J., L.S., Annette Lake and Dorothy Montgomery prepared samples and collated data. F.E.v.L. designed the Dutch NKI study and obtained financial support. N.S.R. and M.d.B. were involved in identification and inclusion of Dutch cases, study design, review board approval and clinical implementation. A.B. coordinated collection and preparation of the NKI samples. A.F., K.H., A.E., E.P.v.S. and K.S.R. provided samples and data from German cases and controls. A.D., I.M.N. and A.v.d.B. collected samples and data from cHL cases ascertained through Groningen University. R.H., H.W., T.v.W. and R.v.E. performed ascertainment and collection of control samples from The Netherlands. H.H., M.M., K.R., L.P.R., K.E.S., H.-O.A., B.G., Daniel Molin, S.H.-D., K.M.S. and E.T.C. provided samples and data from the SCALE study in Denmark and Sweden. S.H.-D. analyzed samples and provided data from Danish cHL cases. All authors contributed to the final paper. R.F.J. and H.H. contributed equally to the paper and should be considered to have equal positional status in the author list.

Correspondence to Richard S Houlston.

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