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Lookup NU author(s): Dr Nicola Sunter, Professor Graham Jackson, Dr Thahira Rahman, Professor James Allan
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
B-cell malignancies (BCM) originate from the same cell of origin, but at different maturation stages and have distinct clinical phenotypes. Although genetic risk variants for individual BCMs have been identified, an agnostic, genome-wide search for shared genetic susceptibility has not been performed. We explored genome-wide association studies of chronic lymphocytic leukaemia (CLL, N = 1,842), Hodgkin lymphoma (HL, N = 1,465) and multiple myeloma (MM, N = 3,790). We identified a novel pleiotropic risk locus at 3q22.2 (NCK1, rs11715604, P = 1.60 x 10(-9)) with opposing effects between CLL (P = 1.97 x 10(-8)) and HL (P = 3.31 x 10(-3)). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 x 10(-12)) was associated with increased CLL and HL risk (P = 4.68 x 10-12), and reduced MM risk (P = 1.12 x 10(-2)), and Gly70 in HLA- DQB1 (P = 3.15 x 10(-10)) showed opposing effects between CLL (P = 3.52 x 10(-3)) and HL (P = 3.41 x 10(-9)). By integrating eQTL, Hi-C and ChIP-seq data, we show that the pleiotropic risk loci are enriched for B-cell regulatory elements, as well as an over-representation of binding of key B-cell transcription factors. These data identify shared biological pathways influencing the development of CLL, HL and MM. The identification of these risk loci furthers our understanding of the aetiological basis of BCMs.
Author(s): Law PJ, Sud A, Mitchell JS, Henrion M, Orlando G, Lenive O, Broderick P, Speedy HE, Johnson DC, Kaiser M, Weinhold N, Cooke R, Sunter NJ, Jackson GH, Summerfield G, Harris RJ, Pettitt AR, Allsup DJ, Carmichael J, Bailey JR, Pratt G, Rahman T, Pepper C, Fegan C, von Strandmann EP, Engert A, Försti A, Chen BW, da Silva MI, Thomsen H, Hoffmann P, Noethen MM, Eisele L, Jöckel KH, Allan JM, Swerdlow AJ, Goldschmidt H, Catovsky D, Morgan GJ, Hemminki K, Houlston RS
Publication type: Article
Publication status: Published
Journal: Scientific Reports
Year: 2017
Volume: 7
Online publication date: 23/01/2017
Acceptance date: 14/12/2016
Date deposited: 16/03/2017
ISSN (electronic): 2045-2322
Publisher: Nature Publishing Group
URL: https://doi.org/10.1038/srep41071
DOI: 10.1038/srep41071
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