Meta-analysis of new genome-wide association studies of colorectal cancer risk
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Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10−8). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10−5). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10−4). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.
KeywordsSingle Nucleotide Polymorphism Colorectal Cancer Risk Wellcome Trust Case Control Consortium Average Call Rate Colon Cancer Family Registry
The authors thank Dr. Ian Tomlinson at the Wellcome Trust Centre for Human Genetics, Oxford, UK, Dr. Richard Houlston at the Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK, and Dr. Malcolm Dunlop at Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and Human Genetics Unit, Medical Research Council, Edinburgh, UK for providing access to GWAS summary statistics of the Colorectal Tumour Gene Identification Consortium (CORGI) and allow us to use these results to inform the ranking of the SNP selection for the replication.
ARCTIC: This work was supported by the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. TJH and BWZ are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research.
CCFR: This work was supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome-wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The following Colon CFR centers contributed data to this manuscript and were supported by the following sources: Australasian Colorectal Cancer Family Registry (U01 CA097735), Familial Colorectal Neoplasia Collaborative Group (U01 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800), Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783), Seattle Colorectal Cancer Family Registry (U01 CA074794), University of Hawaii Colorectal Cancer Family Registry (U01 CA074806).
DACHS: This work was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). We thank all participants and cooperating clinicians, and Ute Handte-Daub, Belinda-Su Kaspereit and Ursula Eilber for excellent technical assistance.
DALS: This work was supported by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (R01 CA48998 to MLS).
DALS, PLCO and WHI GWAS: Funding for the genome-wide scan of DALS, PLCO, and DALS was provided by the National Cancer Institute, Institutes of Health, U.S. Department of Health and Human Services (R01 CA059045 to UP). CMH was supported by a training grant from the National Cancer Institute, Institutes of Health, U.S. Department of Health and Human Services (R25 CA094880).
FRENCH: This work was funded by a regional Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Françaises dans la LUtte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique and the Ligue Régionale Contre le Cancer (LRCC).
GECCO: Funding for GECCO infrastructure is supported by National Cancer Institute, Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088 to UP).
HPFS: This work was supported by the National Institutes of Health (P01 CA 055075 to C.S.F., R01 137178 to A.T.C., and P50 CA 127003 to C.S.F.). We acknowledge Patrice Soule and Hardeep Ranu for genotyping at the Dana-Farber Harvard Cancer Center High Throughput Polymorphism Core under the supervision of David J. Hunter, and Carolyn Guo for programming assistance.
MECC: This work was supported by the National Institutes of Health, U.S. Department of Health and Human Services (R01 CA81488 to SBG and GR).
NFCCR: This work was supported by an Interdisciplinary Health Research Team award from the Canadian Institutes of Health Research (CRT 43821); the National Institutes of Health, U.S. Department of Health and Human Services (U01 CA74783); and National Cancer Institute of Canada grants (18223 and 18226). The authors wish to acknowledge the contribution of Alexandre Belisle and the genotyping team of the McGill University and Génome Québec Innovation Centre, Montréal, Canada, for genotyping the Sequenom panel in the NFCCR samples.
NHS: This work was supported by the National Institutes of Health (P01 CA 087969 to ELG, R01 137178 to ATC, and P50 CA 127003 to CSF). We acknowledge Patrice Soule and Hardeep Ranu for genotyping at the Dana-Farber Harvard Cancer Center High Throughput Polymorphism Core under the supervision of David J. Hunter, and Carolyn Guo for programming assistance.
PHS: We acknowledge Patrice Soule and Hardeep Ranu for genotyping at the Dana-Farber Harvard Cancer Center High Throughput Polymorphism Core under the supervision of David J. Hunter, and Haiyan Zhang for programming assistance.
PLCO: This research was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services. The authors thank Drs. Christine Berg and Philip Prorok at the Division of Cancer Prevention at the National Cancer Institute, and investigators and staff from the screening centers of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, Mr. Thomas Riley and staff at Information Management Services, Inc., Ms. Barbara O’Brien and staff at Westat, Inc., and Mr. Tim Sheehy and staff at SAIC-Frederick. Most importantly, we acknowledge the study participants for their contributions to making this study possible.
Control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer scan were supported by the Intramural Research Program of the National Cancer Institute. The datasets used in this analysis were accessed with appropriate approval through the dbGaP online resource (http://cgems.cancer.gov/data_access.html) through dbGaP accession number 000207v.1p1.c1 (National Cancer Institute 2009; Yeager et al. 2007). Control samples were also genotyped as part of the GWAS of Lung Cancer and Smoking. Funding for this work was provided through the National Institutes of Health, Genes, Environment and Health Initiative [NIH GEI] (Z01 CP 010200). The human subjects participating in the GWAS are derived from the Prostate, Lung, Colon and Ovarian Screening Trial and the study is supported by intramural resources of the National Cancer Institute. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NHI GEI (U01 HG 004438). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number ph000093.v2.p2.c1.
WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221, and 268200764316C.
The authors wish to acknowledge Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller at the (National Heart, Lung, and Blood Institute, Bethesda, Maryland); the following Clinical Coordinating Center investigators: Kooperberg (Fred Hutchinson Cancer Research Center, Seattle, WA) Ross Prentice, Garnet Anderson, Andrea LaCroix, Charles Kooperberg, (Medical Research Labs, Highland Heights, KY) Evan Stein, and (University of California at San Francisco, San Francisco, CA) Steven Cummings; and (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker with the Women’s Health Initiative Memory Study.
In addition, we wish to acknowledge the following Clinical Center investigators: Sylvia Wassertheil-Smoller (Albert Einstein College of Medicine, Bronx, NY); Haleh Sangi-Haghpeykar (Baylor College of Medicine, Houston, TX); JoAnn E. Manson (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA); Charles B. Eaton (Brown University, Providence, RI); Lawrence S. Phillips (Emory University, Atlanta, GA); Shirley Beresford (Fred Hutchinson Cancer Research Center, Seattle, WA); Lisa Martin (George Washington University Medical Center, Washington, DC); Rowan Chlebowski (Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA); Erin LeBlanc (Kaiser Permanente Center for Health Research, Portland, OR); Bette Caan (Kaiser Permanente Division of Research, Oakland, CA); Jane Morley Kotchen (Medical College of Wisconsin, Milwaukee, WI); Barbara V. Howard (MedStar Research Institute/Howard University, Washington, DC); Linda Van Horn (Northwestern University, Chicago/Evanston, IL); Henry Black (Rush Medical Center, Chicago, IL); Marcia L. Stefanick (Stanford Prevention Research Center, Stanford, CA); Dorothy Lane (State University of New York at Stony Brook, Stony Brook, NY); Rebecca Jackson (The Ohio State University, Columbus, OH); Cora E. Lewis (University of Alabama at Birmingham, Birmingham, AL); Cynthia A. Thomson (University of Arizona, Tucson/Phoenix, AZ); Jean Wactawski-Wende (University at Buffalo, Buffalo, NY); John Robbins (University of California at Davis, Sacramento, CA); F. Allan Hubbell (University of California at Irvine, CA); Lauren Nathan (University of California at Los Angeles, Los Angeles, CA); Robert D. Langer (University of California at San Diego, LaJolla/Chula Vista, CA); Margery Gass (University of Cincinnati, Cincinnati, OH); Marian Limacher (University of Florida, Gainesville/Jacksonville, FL); J. David Curb (University of Hawaii, Honolulu, HI); Robert Wallace (University of Iowa, Iowa City/Davenport, IA); Judith Ockene (University of Massachusetts/Fallon Clinic, Worcester, MA); Norman Lasser (University of Medicine and Dentistry of New Jersey, Newark, NJ); Mary Jo O’Sullivan (University of Miami, Miami, FL); Karen Margolis (University of Minnesota, Minneapolis, MN); Robert Brunner (University of Nevada, Reno, NV); Gerardo Heiss (University of North Carolina, Chapel Hill, NC); Lewis Kuller (University of Pittsburgh, Pittsburgh, PA); Karen C. Johnson (University of Tennessee Health Science Center, Memphis, TN); Robert Brzyski (University of Texas Health Science Center, San Antonio, TX); Gloria E. Sarto (University of Wisconsin, Madison, WI); Mara Vitolins (Wake Forest University School of Medicine, Winston-Salem, NC); Michael S. Simon (Wayne State University School of Medicine/Hutzel Hospital, Detroit, MI).
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