title: Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer.
abstract: Genome-wide association studies (GWAS) of urinary bladder cancer (UBC) have yielded common variants at 12 loci that associate with risk of the disease. We report here the results of a GWAS of UBC including 1670 UBC cases and 90 180 controls, followed by replication analysis in additional 5266 UBC cases and 10 456 controls. We tested a dataset containing 34.2 million variants, generated by imputation based on whole-genome sequencing of 2230 Icelanders. Several correlated variants at 20p12, represented by rs62185668, show genome-wide significant association with UBC after combining discovery and replication results (OR = 1.19, P = 1.5 × 10(-11) for rs62185668-A, minor allele frequency = 23.6%). The variants are located in a non-coding region approximately 300 kb upstream from the JAG1 gene, an important component of the Notch signaling pathways that may be oncogenic or tumor suppressive in several forms of cancer. Our results add to the growing number of UBC risk variants discovered through GWAS.
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland thorunn.rafnar@decode.is kstefans@decode.is.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: Department for Health Evidence Department of Genetics and.
authors.forename: Sita H
authors.initials: SH
authors.lastname: Vermeulen
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland School of Engineering and Natural Sciences and.
authors.forename: Hannes
authors.initials: H
authors.lastname: Helgason
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Jona
authors.initials: J
authors.lastname: Saemundsdottir
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Sigurjon A
authors.initials: SA
authors.lastname: Gudjonsson
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Julius
authors.initials: J
authors.lastname: Gudmundsson
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Hrefna
authors.initials: H
authors.lastname: Johannsdottir
authors.affiliation: Department of Medicine.
authors.forename: Kristin
authors.initials: K
authors.lastname: Alexiusdottir
authors.affiliation: Department of Pathology.
authors.forename: Vigdis
authors.initials: V
authors.lastname: Petursdottir
authors.affiliation: Department of Pathology.
authors.forename: Sigfus
authors.initials: S
authors.lastname: Nikulasson
authors.affiliation: Department of Urology and.
authors.forename: Gudmundur
authors.initials: G
authors.lastname: Geirsson
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland Department of Surgery, Landspitali-University Hospital, Reykjavik 101, Iceland.
authors.forename: Thorvaldur
authors.initials: T
authors.lastname: Jonsson
authors.affiliation: Department for Health Evidence Comprehensive Cancer Center The Netherlands, Utrecht, The Netherlands.
authors.forename: Katja K H
authors.initials: KK
authors.lastname: Aben
authors.affiliation: Department for Health Evidence.
authors.forename: Anne J
authors.initials: AJ
authors.lastname: Grotenhuis
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Verhaegh
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Dudek
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
authors.forename: J Alfred
authors.initials: JA
authors.lastname: Witjes
authors.affiliation: Department of Urology, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Antoine G
authors.initials: AG
authors.lastname: van der Heijden
authors.affiliation: Department for Health Evidence.
authors.forename: Alina
authors.initials: A
authors.lastname: Vrieling
authors.affiliation: Department for Health Evidence.
authors.forename: Tessel E
authors.initials: TE
authors.lastname: Galesloot
authors.affiliation: Division of Medical Oncolology, Marques de Valdecilla University Hospital, Santander 39008, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: De Juan
authors.affiliation: Division of Medical Oncolology, Ciudad de Coria Hospital, Coria 10800, Spain.
authors.forename: Angeles
authors.initials: A
authors.lastname: Panadero
authors.affiliation: Division of Medical Oncolology, Marques de Valdecilla University Hospital, Santander 39008, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivera
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Hurst
authors.affiliation: Section of Epidemiology & Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.affiliation: Mid Yorkshire NHS Trust, Pinderfields Hospital, Wakefield WF1 4DG, UK.
authors.forename: Sei C
authors.initials: SC
authors.lastname: Sak
authors.affiliation: Christie Hospital NHS Trust, Manchester M20 4BX, UK.
authors.forename: Ananya
authors.initials: A
authors.lastname: Choudhury
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Mark T W
authors.initials: MT
authors.lastname: Teo
authors.affiliation: Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia, Brescia 1-25125, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Arici
authors.affiliation: Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia, Brescia 1-25125, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Carta
authors.affiliation: Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia, Brescia 1-25125, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Toninelli
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm S171 76, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: de Verdier
authors.affiliation: Department of Environmental Epidemiology, National Institute of Environmental Health, Budapest H-1450, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Rudnai
authors.affiliation: Health Department, Environmental Health Center, Babes Bolyai University, Cluj-Napoca 3400, Romania.
authors.forename: Eugene
authors.initials: E
authors.lastname: Gurzau
authors.affiliation: Department of Environmental Health, Regional Authority of Public Health, Banska Bystrica 975 56, Slovakia.
authors.forename: Kvetoslava
authors.initials: K
authors.lastname: Koppova
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam 3000 CA, The Netherlands.
authors.forename: Kirstin A
authors.initials: KA
authors.lastname: van der Keur
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam 3000 CA, The Netherlands.
authors.forename: Irene
authors.initials: I
authors.lastname: Lurkin
authors.affiliation: Department of General Practice, Catholic University of Leuven, Leuven 3000, Belgium.
authors.forename: Mieke
authors.initials: M
authors.lastname: Goossens
authors.affiliation: Leuven University Centre for Cancer Prevention (LUCK), Leuven 3000, Belgium.
authors.forename: Eliane
authors.initials: E
authors.lastname: Kellen
authors.affiliation: Human Genetics Foundation, HuGeF, Torino I-10126, Italy.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Guarrera
authors.affiliation: Human Genetics Foundation, HuGeF, Torino I-10126, Italy Department of Medical Sciences and.
authors.forename: Alessia
authors.initials: A
authors.lastname: Russo
authors.affiliation: Human Genetics Foundation, HuGeF, Torino I-10126, Italy Department of Medical Sciences and.
authors.forename: Rossana
authors.initials: R
authors.lastname: Critelli
authors.affiliation: Human Genetics Foundation, HuGeF, Torino I-10126, Italy Unit of Cancer Epidemiology, University of Torino, Torino 10126, Italy Centre for Cancer Epidemiology and Prevention (CPO Piemonte), Torino 10126, Italy.
authors.forename: Carlotta
authors.initials: C
authors.lastname: Sacerdote
authors.affiliation: Human Genetics Foundation, HuGeF, Torino I-10126, Italy Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Vineis
authors.affiliation: CNRS, UMR 144, Oncologie Moléculaire, Institut Curie, Paris 75248 Cedex 05, France Institut Curie, Centre de Recherche, Paris 75248 Cedex 05, France.
authors.forename: Clémentine
authors.initials: C
authors.lastname: Krucker
authors.affiliation: Department of Epidemiology & Complex Genetics NUTRIM/Faculty of Health, Medicine and Life Sciences Maastricht University, Maastricht 6200 MD, The Netherlands.
authors.forename: Maurice P
authors.initials: MP
authors.lastname: Zeegers
authors.affiliation: Department of Urology, Lukasklinik Neuss, Preussenstr. 64, Neuss 41464, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Gerullis
authors.affiliation: Department of Urology, St.-Josefs-Hospital Dortmund-Hörde, Dortmund 44263, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ovsiannikov
authors.affiliation: Department of Urology, Evangelisches Krankenhaus Paul Gerhardt Foundation, Lutherstadt Wittenberg 06886, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Volkert
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors, Dortmund 44139, Germany.
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors, Dortmund 44139, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Selinski
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland School of Engineering and Natural Sciences and.
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland School of Engineering and Natural Sciences and.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gudbjartsson
authors.affiliation: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm S171 76, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Lindblom
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam 3000 CA, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Zwarthoff
authors.affiliation: Department of Medical and Surgical Specialties, Radiological Sciences and Public Health University of Brescia, Brescia 1-25125, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Porru
authors.affiliation: Leibniz Research Centre for Working Environment and Human Factors, Dortmund 44139, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Golka
authors.affiliation: Department of General Practice, Catholic University of Leuven, Leuven 3000, Belgium Research School Care & Department of General Practice, Maastricht University, Maastricht 6200 MD, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Buntinx
authors.affiliation: Human Genetics Foundation, HuGeF, Torino I-10126, Italy Department of Medical Sciences and.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Matullo
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Centre, Heidelberg D-69120, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Division of Medical Oncology, University of Zaragoza, Zaragoza 50009, Spain.
authors.forename: José I
authors.initials: JI
authors.lastname: Mayordomo
authors.affiliation: Department of Oncology and Pathology, Karolinska Hospital, Stockholm S171 76, Sweden Department of Oncology, Sahlgrenska University Hospital, Goteborg S-413 45, Sweden.
authors.forename: D Gunnar
authors.initials: DG
authors.lastname: Steineck
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Anne E
authors.initials: AE
authors.lastname: Kiltie
authors.affiliation: Department of Urology and.
authors.forename: Eirikur
authors.initials: E
authors.lastname: Jonsson
authors.affiliation: CNRS, UMR 144, Oncologie Moléculaire, Institut Curie, Paris 75248 Cedex 05, France Institut Curie, Centre de Recherche, Paris 75248 Cedex 05, France.
authors.forename: François
authors.initials: F
authors.lastname: Radvanyi
authors.affiliation: Section of Experimental Oncology, Leeds Institute of Cancer and Pathology, St. James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Knowles
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: Department for Health Evidence Department of Urology, Radboud University Medical Center, Nijmegen 6500 HB, The Netherlands.
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.affiliation: deCODE Genetics/AMGEN, Reykjavik 101, Iceland Faculty of Medicine, University of Iceland, Reykjavik 101, Iceland thorunn.rafnar@decode.is kstefans@decode.is.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002135:Calcium-Binding Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D000072099:Serrate-Jagged Proteins; D001749:Urinary Bladder Neoplasms / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins