title: A new GWAS and meta-analysis with 1000Genomes imputation identifies novel risk variants for colorectal cancer.
abstract: Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 (P = 1.21 × 10(-8), odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P = 5.06 × 10(-8); OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1. Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P = 7.01 × 10(-8); OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Nada A
authors.initials: NA
authors.lastname: Al-Tassan
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Whiffin
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Fay J
authors.initials: FJ
authors.lastname: Hosking
authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK.
authors.forename: Claire
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authors.lastname: Palles
authors.affiliation: Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Farrington
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Dobbins
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: Rebecca
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authors.lastname: Harris
authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK.
authors.forename: Maggie
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authors.lastname: Gorman
authors.affiliation: 1] Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK [2] The Roslin Institute, University of Edinburgh, Easter Bush, Roslin, EH25 9RG, UK.
authors.forename: Albert
authors.initials: A
authors.lastname: Tenesa
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Meyer
authors.affiliation: Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh 11211, Saudi Arabia.
authors.forename: Salma M
authors.initials: SM
authors.lastname: Wakil
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
authors.forename: Ben
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authors.lastname: Kinnersley
authors.affiliation: Centre for Population Health Sciences, University of Edinburgh, Edinburgh, EH8 9AG, UK.
authors.forename: Harry
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authors.lastname: Campbell
authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK.
authors.forename: Lynn
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authors.lastname: Martin
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Smith
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
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authors.lastname: Idziaszczyk
authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK.
authors.forename: Ella
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authors.lastname: Barclay
authors.affiliation: CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Oxford, OX3 7DQ, UK.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Maughan
authors.affiliation: MRC Clinical Trials Unit, Aviation House, 125 Kingsway, London, WC2B 6NH, UK.
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authors.lastname: Kaplan
authors.affiliation: Oxford Cancer Centre, Department of Oncology, University of Oxford, Churchill Hospital, Old Road, Headington, Oxford, OX3 7LE, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Kerr
authors.affiliation: Nuffield Department of Clinical Laboratory Sciences, University of Oxford, John Radcliffe Hospital, Headley Way, Oxford, OX3 9DU, UK.
authors.forename: David
authors.initials: D
authors.lastname: Kerr
authors.affiliation: 1] Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The Univers‡ity of Melbourne, Victoria, Australia [2] Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchannan
authors.affiliation: Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
authors.forename: Aung Ko
authors.initials: AK
authors.lastname: Win
authors.affiliation: Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
authors.forename: John
authors.initials: J
authors.lastname: Hopper
authors.affiliation: Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia.
authors.forename: Mark
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authors.lastname: Jenkins
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
authors.forename: Steve
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authors.lastname: Gallinger
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: David
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authors.lastname: Conti
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Schumacher
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.affiliation: Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK.
authors.forename: Malcolm G
authors.initials: MG
authors.lastname: Dunlop
authors.affiliation: Wellcome Trust Centre for Human Genetics and NIHR Comprehensive Biomedical Research Centre, Oxford, UK.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Tomlinson
authors.affiliation: Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: Jeremy P
authors.initials: JP
authors.lastname: Cheadle
authors.affiliation: Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
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mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002874:Chromosome Mapping; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C491001:FOXL1 protein, human; D051858:Forkhead Transcription Factors; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor