title: A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study.
abstract: Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Schmit
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Fredrick R
authors.initials: FR
authors.lastname: Schumacher
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.affiliation: Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA.
authors.forename: Leon
authors.initials: L
authors.lastname: Raskin
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel.
authors.forename: Flavio
authors.initials: F
authors.lastname: Lejbkowicz
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel.
authors.forename: Mila
authors.initials: M
authors.lastname: Pinchev
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel.
authors.forename: Hedy S
authors.initials: HS
authors.lastname: Rennert
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.affiliation: Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA.
authors.forename: Noralane M
authors.initials: NM
authors.lastname: Lindor
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Loic
authors.initials: L
authors.lastname: Le Marchand
authors.affiliation: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.affiliation: Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and.
authors.forename: Polly A
authors.initials: PA
authors.lastname: Newcomb
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Shu-Chen
authors.initials: SC
authors.lastname: Huang
authors.affiliation: Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Gad
authors.initials: G
authors.lastname: Rennert
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.affiliation: USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA, Vanderbilt Epidemiology Center, Vanderbilt University, Nashville, TN 37232, USA, Department of Community Medicine and Epidemiology, Carmel Medical Center, Haifa, Israel, Clalit Health Services, National Cancer Control Center, Haifa, Israel, Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia, Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Victoria, Australia, Department of Health Science Research, Mayo Clinic Arizona, Scottsdale, 8525 AZ, USA, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada, Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel sgruber@usc.edu.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gruber
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis; D016022:Case-Control Studies; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors