Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci
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 performe...
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| Main Authors: | , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
23 January 2017
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| In: |
Scientific reports
Year: 2017, Volume: 7 |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/srep41071 |
| Online Access: | Verlag, kostenfrei, Volltext: http://dx.doi.org/10.1038/srep41071 Verlag, kostenfrei, Volltext: https://www.nature.com/articles/srep41071 
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| Author Notes: | Philip J. Law, Amit Sud, Jonathan S. Mitchell, Marc Henrion, Giulia Orlando, Oleg Lenive, Peter Broderick, Helen E. Speedy, David C. Johnson, Martin Kaiser, Niels Weinhold, Rosie Cooke, Nicola J. Sunter, Graham H. Jackson, Geoffrey Summerfield, Robert J. Harris, Andrew R. Pettitt, David J. Allsup, Jonathan Carmichael, James R. Bailey, Guy Pratt, Thahira Rahman, Chris Pepper, Chris Fegan, Elke Pogge von Strandmann, Andreas Engert, Asta Försti, Bowang Chen, Miguel Inacio da Silva Filho, Hauke Thomsen, Per Hoffmann, Markus M. Noethen, Lewin Eisele, Karl-Heinz Jöckel, James M. Allan, Anthony J. Swerdlow, Hartmut Goldschmidt, Daniel Catovsky, Gareth J. Morgan, Kari Hemminki & Richard S. Houlston |
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| 245 | 1 | 0 | |a Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci |c Philip J. Law, Amit Sud, Jonathan S. Mitchell, Marc Henrion, Giulia Orlando, Oleg Lenive, Peter Broderick, Helen E. Speedy, David C. Johnson, Martin Kaiser, Niels Weinhold, Rosie Cooke, Nicola J. Sunter, Graham H. Jackson, Geoffrey Summerfield, Robert J. Harris, Andrew R. Pettitt, David J. Allsup, Jonathan Carmichael, James R. Bailey, Guy Pratt, Thahira Rahman, Chris Pepper, Chris Fegan, Elke Pogge von Strandmann, Andreas Engert, Asta Försti, Bowang Chen, Miguel Inacio da Silva Filho, Hauke Thomsen, Per Hoffmann, Markus M. Noethen, Lewin Eisele, Karl-Heinz Jöckel, James M. Allan, Anthony J. Swerdlow, Hartmut Goldschmidt, Daniel Catovsky, Gareth J. Morgan, Kari Hemminki & Richard S. Houlston |
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| 520 | |a 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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