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A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia

Abstract

Genome-wide association studies (GWAS) of chronic lymphocytic leukemia (CLL) have shown that common genetic variation contributes to the heritable risk of CLL. To identify additional CLL susceptibility loci, we conducted a GWAS and performed a meta-analysis with a published GWAS totaling 1,739 individuals with CLL (cases) and 5,199 controls with validation in an additional 1,144 cases and 3,151 controls. A combined analysis identified new susceptibility loci mapping to 3q26.2 (rs10936599, P = 1.74 × 10−9), 4q26 (rs6858698, P = 3.07 × 10−9), 6q25.2 (IPCEF1, rs2236256, P = 1.50 × 10−10) and 7q31.33 (POT1, rs17246404, P = 3.40 × 10−8). Additionally, we identified a promising association at 5p15.33 (CLPTM1L, rs31490, P = 1.72 × 10−7) and validated recently reported putative associations at 5p15.33 (TERT, rs10069690, P = 1.12 × 10−10) and 8q22.3 (rs2511714, P = 2.90 × 10−9). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CLL.

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Figure 1: Plots of ORs for five variants associated with CLL.
Figure 2: Regional plots of association results, recombination rates and chromatin state segmentation tracks for five CLL risk loci.

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Acknowledgements

Leukaemia and Lymphoma Research provided principal funding for the study (LRF05001 and LRF06002). We acknowledge support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Arbib Fund. We also acknowledge National Health Service funding to the Royal Marsden/Institute of Cancer Research; National Institute for Health Research Biomedical Research Centre. The study made use of genotyping data on the 1958 Birth Cohort; a full list of the investigators who contributed to the generation of these data is available at http://www.wtccc.org.uk/. We thank L. Padyukov (Karolinska Institutet) and the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) group for providing control samples from the Swedish population for the Swedish replication study. We are grateful to all clinicians for their involvement in patient ascertainment. This study makes use of data generated by the Wellcome Trust Case-Control Consortium 1 and 2. A full list of the investigators who contributed to the generation of the data is available at http://www.wtccc.org.uk/. We are grateful to all investigators and all the patients and individuals for their participation. We also thank the clinicians, other hospital staff and study staff that contributed to the blood sample and data collection for this study.

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Authors

Contributions

R.S.H. obtained financial support, designed the project and provided overall project management. R.S.H. drafted the manuscript. H.E.S. performed project management and supervised genotyping. M.C.D.B. performed bioinformatic and statistical analyses. G.P.S. and A.H. performed genotyping. Y.W. and M.C.D.B. performed imputation analysis. D.C. and R.S.H. established the International CLL Linkage Consortium (ICLLLC). C.D. and D.C. performed recruitment of samples. In Sweden, L.M. performed sample collection and prepared DNA; R.R. performed collection of all cases and G.J. and K.E.S. performed sample collection in the Scandinavian Lymphoma Etiology (SCALE) study; and G.R. performed telomere analysis. In Newcastle, J.M.A. and D.J.A. conceived of the NCLLC; J.M.A. obtained financial support, supervised laboratory management and oversaw genotyping of cases with NCLLC; N.J.S. performed sample management of cases; A.G.H. developed the Newcastle Haematology Biobank, incorporating NCLLC; and T.M.-F., G.H.J., G.S., R.J.H., A.R.P., D.J.A., J.R.B., G.P., C.P. and C.F. developed protocols for recruitment of individuals with CLL and sample acquisition and performed sample collection of cases. In Leicester, M.J.S.D. performed overall management, collection and processing of samples; and S.J. and A.M. performed DNA extractions and IGVH mutation assays. All authors contributed to the final paper.

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Correspondence to Richard S Houlston.

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Speedy, H., Di Bernardo, M., Sava, G. et al. A genome-wide association study identifies multiple susceptibility loci for chronic lymphocytic leukemia. Nat Genet 46, 56–60 (2014). https://doi.org/10.1038/ng.2843

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