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


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 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.

SUBMITTER: Law PJ 

PROVIDER: S-EPMC5253627 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Law Philip J PJ   Sud Amit A   Mitchell Jonathan S JS   Henrion Marc M   Orlando Giulia G   Lenive Oleg O   Broderick Peter P   Speedy Helen E HE   Johnson David C DC   Kaiser Martin M   Weinhold Niels N   Cooke Rosie R   Sunter Nicola J NJ   Jackson Graham H GH   Summerfield Geoffrey G   Harris Robert J RJ   Pettitt Andrew R AR   Allsup David J DJ   Carmichael Jonathan J   Bailey James R JR   Pratt Guy G   Rahman Thahira T   Pepper Chris C   Fegan Chris C   von Strandmann Elke Pogge EP   Engert Andreas A   Försti Asta A   Chen Bowang B   Filho Miguel Inacio da Silva MI   Thomsen Hauke H   Hoffmann Per P   Noethen Markus M MM   Eisele Lewin L   Jöckel Karl-Heinz KH   Allan James M JM   Swerdlow Anthony J AJ   Goldschmidt Hartmut H   Catovsky Daniel D   Morgan Gareth J GJ   Hemminki Kari K   Houlston Richard S RS  

Scientific reports 20170123


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 pleiotrop  ...[more]

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