Law, Philip J., Sud, Amit ORCID: 0000-0002-6133-0164, Mitchell, Jonathan S., Henrion, Marc ORCID: 0000-0003-1242-839X, Orlando, Giulia, Lenive, Oleg, Broderick, Peter, Speedy, Helen E., Johnson, David C., Kaiser, Martin, Weinhold, Niels, Cooke, Rosie, Sunter, Nicola J., Jackson, Graham H., Summerfield, Geoffrey, Harris, Robert J., Pettitt, Andrew R., Allsup, David J., Carmichael, Jonathan, Bailey, James R., Pratt, Guy, Rahman, Thahira, Pepper, Chris, Fegan, Chris, von Strandmann, Elke Pogge, Engert, Andreas, Foersti, Asta, Chen, Bowang, da Silva Filho, Miguel Inacio, Thomsen, Hauke ORCID: 0000-0001-5951-3116, Hoffmann, Per, Noethen, Markus M., Eisele, Lewin, Joeckel, Karl-Heinz, Allan, James M., Swerdlow, Anthony J., Goldschmidt, Hartmut, Catovsky, Daniel, Morgan, Gareth J., Hemminki, Kari and Houlston, Richard S. (2017). Genome-wide association analysis of chronic lymphocytic leukaemia, Hodgkin lymphoma and multiple myeloma identifies pleiotropic risk loci. Sci Rep, 7. LONDON: NATURE PUBLISHING GROUP. ISSN 2045-2322

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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 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Law, Philip J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sud, AmitUNSPECIFIEDorcid.org/0000-0002-6133-0164UNSPECIFIED
Mitchell, Jonathan S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Henrion, MarcUNSPECIFIEDorcid.org/0000-0003-1242-839XUNSPECIFIED
Orlando, GiuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lenive, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Broderick, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speedy, Helen E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Johnson, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kaiser, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weinhold, NielsUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cooke, RosieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sunter, Nicola J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jackson, Graham H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Summerfield, GeoffreyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Harris, Robert J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pettitt, Andrew R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allsup, David J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carmichael, JonathanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bailey, James R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pratt, GuyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rahman, ThahiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pepper, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fegan, ChrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Strandmann, Elke PoggeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engert, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Foersti, AstaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, BowangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
da Silva Filho, Miguel InacioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomsen, HaukeUNSPECIFIEDorcid.org/0000-0001-5951-3116UNSPECIFIED
Hoffmann, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eisele, LewinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joeckel, Karl-HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Allan, James M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Swerdlow, Anthony J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goldschmidt, HartmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Catovsky, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morgan, Gareth J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hemminki, KariUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Houlston, Richard S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-242295
DOI: 10.1038/srep41071
Journal or Publication Title: Sci Rep
Volume: 7
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2045-2322
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
T-CELL-ACTIVATION; CAPTURE HI-C; SUSCEPTIBILITY LOCI; GENE-EXPRESSION; FUNCTIONAL VARIATION; FOLLICULAR LYMPHOMA; COMMON VARIATION; TARGETING BCL2; HLA REGION; CANCERMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/24229

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