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Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci

Law, Philip J.; Sud, Amit LU ; Mitchell, Jonathan S; Henrion, Marc; Orlando, Giulia; Lenive, Oleg; Broderick, Peter; Speedy, Helen E; Johnson, David C. and Kaiser, Martin, et al. (2017) In Scientific Reports 7.
Abstract

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 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within... (More)

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 × 10-9) with opposing effects between CLL (P = 1.97 × 10-8) and HL (P = 3.31 × 10-3). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10-12) was associated with increased CLL and HL risk (P = 4.68 × 10-12), and reduced MM risk (P = 1.12 × 10-2), and Gly70 in HLA-DQB1 (P = 3.15 × 10-10) showed opposing effects between CLL (P = 3.52 × 10-3) and HL (P = 3.41 × 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.

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@article{178a0b4b-70ee-43fe-a5f7-a3b566af6920,
  abstract     = {<p>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 × 10<sup>-9</sup>) with opposing effects between CLL (P = 1.97 × 10<sup>-8</sup>) and HL (P = 3.31 × 10<sup>-3</sup>). Eight established non-HLA risk loci showed pleiotropic associations. Within the HLA region, Ser37 + Phe37 in HLA-DRB1 (P = 1.84 × 10<sup>-12</sup>) was associated with increased CLL and HL risk (P = 4.68 × 10<sup>-12</sup>), and reduced MM risk (P = 1.12 × 10<sup>-2</sup>), and Gly70 in HLA-DQB1 (P = 3.15 × 10<sup>-10</sup>) showed opposing effects between CLL (P = 3.52 × 10<sup>-3</sup>) and HL (P = 3.41 × 10<sup>-9</sup>). 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.</p>},
  articleno    = {41071},
  author       = {Law, Philip J. and Sud, Amit and Mitchell, Jonathan S and Henrion, Marc and Orlando, Giulia and Lenive, Oleg and Broderick, Peter and Speedy, Helen E and Johnson, David C. and Kaiser, Martin and Weinhold, Niels and Cooke, Rosie and Sunter, Nicola J. and Jackson, Graham H. and Summerfield, Geoffrey and Harris, Robert J. and Pettitt, Andrew R. and Allsup, David J. and Carmichael, Jonathan and Bailey, James R. and Pratt, Guy and Rahman, Thahira and Pepper, Chris and Fegan, Chris and von Strandmann, Elke Pogge and Engert, Andreas and Försti, Asta and Chen, Bowang and Filho, Miguel Inacio da Silva and Thomsen, Hauke and Hoffmann, Per and Noethen, Markus M. and Eisele, Lewin and Jöckel, Karl-Heinz and Allan, James M. and Swerdlow, Anthony J and Goldschmidt, Hartmut and Catovsky, Daniel and Morgan, Gareth J. and Hemminki, Kari and Houlston, Richard S.},
  issn         = {2045-2322},
  language     = {eng},
  month        = {01},
  publisher    = {Nature Publishing Group},
  series       = {Scientific Reports},
  title        = {Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci},
  url          = {http://dx.doi.org/10.1038/srep41071},
  volume       = {7},
  year         = {2017},
}