title: Genome-wide association study identifies multiple susceptibility loci for multiple myeloma.
abstract: Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a new GWAS and perform replication analyses resulting in 9,866 cases and 239,188 controls. We confirm all nine known risk loci and discover eight new loci at 6p22.3 (rs34229995, P=1.31 × 10(-8)), 6q21 (rs9372120, P=9.09 × 10(-15)), 7q36.1 (rs7781265, P=9.71 × 10(-9)), 8q24.21 (rs1948915, P=4.20 × 10(-11)), 9p21.3 (rs2811710, P=1.72 × 10(-13)), 10p12.1 (rs2790457, P=1.77 × 10(-8)), 16q23.1 (rs7193541, P=5.00 × 10(-12)) and 20q13.13 (rs6066835, P=1.36 × 10(-13)), which localize in or near to JARID2, ATG5, SMARCD3, CCAT1, CDKN2A, WAC, RFWD3 and PREX1. These findings provide additional support for a polygenic model of MM and insight into the biological basis of tumour development.
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Mitchell
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Ni
authors.initials: N
authors.lastname: Li
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.|Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Weinhold
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, SE-205 02 Malmo, Sweden.
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Mina
authors.initials: M
authors.lastname: Ali
authors.affiliation: Department of Hematology, Erasmus MC Cancer Institute, 3075 EA Rotterdam, The Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: van Duin
authors.affiliation: deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: David C
authors.identifier: 0000-0003-0887-3343
authors.initials: DC
authors.lastname: Johnson
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Bowang
authors.initials: B
authors.lastname: Chen
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Halvarsson
authors.affiliation: deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: Department of Hematology, Erasmus MC Cancer Institute, 3075 EA Rotterdam, The Netherlands.
authors.forename: Rowan
authors.initials: R
authors.lastname: Kuiper
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Owen W
authors.initials: OW
authors.lastname: Stephens
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany.|National Centre of Tumor Diseases, 69120 Heidelberg, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Bertsch
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Peter
authors.identifier: 0000-0002-8348-5829
authors.initials: P
authors.lastname: Broderick
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Chiara
authors.initials: C
authors.lastname: Campo
authors.affiliation: University Clinic of Würzburg, 97080 Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Clinical Trials Research Unit, University of Leeds, Leeds LS2 9PH, UK.
authors.forename: Walter A
authors.initials: WA
authors.lastname: Gregory
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Gullberg
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Marc
authors.identifier: 0000-0003-1242-839X
authors.initials: M
authors.lastname: Henrion
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Hillengass
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.|Division of Medical Genetics, Department of Biomedicine, University of Basel, 4003 Basel, Switzerland.
authors.forename: Per
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK.
authors.forename: Graham H
authors.initials: GH
authors.lastname: Jackson
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Ellinor
authors.initials: E
authors.lastname: Johnsson
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.|Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, SE-221 85 Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Jöud
authors.affiliation: Department of Hematology, Landspitali, National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Sigurður Y
authors.initials: SY
authors.lastname: Kristinsson
authors.affiliation: Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Stig
authors.initials: S
authors.lastname: Lenhoff
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Oleg
authors.initials: O
authors.lastname: Lenive
authors.affiliation: Section of Hematology, Sahlgrenska University Hospital, Gothenburg 413 45, Sweden.
authors.forename: Ulf-Henrik
authors.initials: UH
authors.lastname: Mellqvist
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Migliorini
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.affiliation: Rudbeck Laboratory, Department of Immunology, Pathology and Genetics, Uppsala University, SE-751 05 Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany.
authors.forename: Jolanta
authors.initials: J
authors.lastname: Nickel
authors.affiliation: Institute of Human Genetics, University of Bonn, D-53127 Bonn, Germany.|Department of Genomics, Life &Brain Center, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: Wessex Regional Genetics Laboratory, University of Southampton, Salisbury SP2 8BJ, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Ross
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Miguel Inacio
authors.initials: MI
authors.lastname: da Silva Filho
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Bhairavi
authors.initials: B
authors.lastname: Swaminathan
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Hauke
authors.identifier: 0000-0001-5951-3116
authors.initials: H
authors.lastname: Thomsen
authors.affiliation: Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Turesson
authors.affiliation: Department of Haematology, University Hospital of Copenhagen at Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Annette
authors.initials: A
authors.lastname: Vangsted
authors.affiliation: National Research Centre for the Working Environment, DK-2100 Copenhagen, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Box 8905, N-7491 Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Walker
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Wihlborg
authors.affiliation: Department of Hematology, Erasmus MC Cancer Institute, 3075 EA Rotterdam, The Netherlands.
authors.forename: Annemiek
authors.initials: A
authors.lastname: Broyl
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Faith E
authors.initials: FE
authors.lastname: Davies
authors.affiliation: deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: Department of Internal Medicine III, University of Ulm, D-89081 Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Langer
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.|Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Markus
authors.identifier: 0000-0002-7715-4548
authors.initials: M
authors.lastname: Hansson
authors.affiliation: Division of Molecular Pathology, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Kaiser
authors.affiliation: Department of Hematology, Erasmus MC Cancer Institute, 3075 EA Rotterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Sonneveld
authors.affiliation: deCODE Genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.affiliation: Department of Internal Medicine V, University of Heidelberg, 69117 Heidelberg, Germany.|National Centre of Tumor Diseases, 69120 Heidelberg, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Goldschmidt
authors.affiliation: German Cancer Research Center, 69120 Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, SE-205 02 Malmo, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, BMC B13, SE-221 84 Lund, Sweden.|Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, SE-221 85 Lund, Sweden.|Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D016022:Case-Control Studies; D002868:Chromosomal Proteins, Non-Histone; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics; D006801:Humans; D009101:Multiple Myeloma / Q000235:genetics*; D063151:Polycomb Repressive Complex 2 / Q000235:genetics; D062085:RNA, Long Noncoding / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: C502778:ATG5 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071187:Autophagy-Related Protein 5; C579842:CCAT1 long noncoding RNA, human; C000614131:CDKN2A protein, human; D002868:Chromosomal Proteins, Non-Histone; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; D020662:Guanine Nucleotide Exchange Factors; C547777:JARID2 protein, human; C453280:PREX1 protein, human; D062085:RNA, Long Noncoding; C491649:SMARCD3 protein, human; D014157:Transcription Factors; C574643:WAC protein, human; D063151:Polycomb Repressive Complex 2; C549038:RFWD3 protein, human; D044767:Ubiquitin-Protein Ligases