title: 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.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Law
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Amit
authors.initials: A
authors.lastname: Sud
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Mitchell
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Marc
authors.initials: M
authors.lastname: Henrion
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Orlando
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Lenive
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Speedy
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Niels
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Rosie
authors.initials: R
authors.lastname: Cooke
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Sunter
authors.affiliation: Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: Department of Haematology, Queen Elizabeth Hospital, Gateshead, Newcastle upon Tyne, UK.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Summerfield
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Harris
authors.affiliation: Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pettitt
authors.affiliation: Queens Centre for Haematology and Oncology, Castle Hill Hospital, Hull and East Yorkshire NHS Trust, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Allsup
authors.affiliation: Queens Centre for Haematology and Oncology, Castle Hill Hospital, Hull and East Yorkshire NHS Trust, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Carmichael
authors.affiliation: Queens Centre for Haematology and Oncology, Castle Hill Hospital, Hull and East Yorkshire NHS Trust, UK.
authors.forename: James R
authors.initials: JR
authors.lastname: Bailey
authors.affiliation: Department of Haematology, Birmingham Heartlands Hospital, Birmingham, UK.
authors.forename: Guy
authors.initials: G
authors.lastname: Pratt
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Thahira
authors.initials: T
authors.lastname: Rahman
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.affiliation: Cardiff and Vale National Health Service Trust, Heath Park, Cardiff, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Fegan
authors.affiliation: Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Elke Pogge
authors.initials: EP
authors.lastname: von Strandmann
authors.affiliation: Department of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Engert
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.|Centre for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Miguel Inacio da Silva
authors.initials: MI
authors.lastname: Filho
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.
authors.forename: Hauke
authors.initials: H
authors.lastname: Thomsen
authors.affiliation: Institute of Human Genetics, University of Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Germany.|Department of Genomics, Life &Brain Center, University of Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Noethen
authors.affiliation: University of Duisburg-Essen, Essen, Germany.
authors.forename: Lewin
authors.initials: L
authors.lastname: Eisele
authors.affiliation: University of Duisburg-Essen, Essen, Germany.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Jöckel
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.|Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Swerdlow
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany.|National Center of Tumor Diseases, Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg, Germany.|Centre for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.|Division of Molecular Pathology, The Institute of Cancer Research, London, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000368:Aged; D005260:Female; D058685:Genetic Pleiotropy / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D059866:HLA-DQ beta-Chains / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics* / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D059811:HLA-DRB1 Chains; C078332:Nck protein; D015513:Oncogene Proteins