Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
Bibliographical noteFunding Information:
Colorectal Transdisciplinary Study (CORECT): The CORECT Study was supported by the National Cancer Institute/ National Institutes of Health (NCI/NIH), US Department of Health and Human Services (grant numbers U19 CA148107, R01 CA81488, P30 CA014089, R01 CA197350, P01 CA196569, R01 CA201407), and National Institutes of Environmental Health Sciences, National Institutes of Health (grant number T32 ES013678). The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was supported by US Public Health Service contracts (N01-CN-45165, N01-RC-45035, N01-RC-37004, and HHSN261201000006C) from the National Cancer Institute. The Cancer Prevention Study-II Nutrition Cohort is funded by the American Cancer Society. ColoCare: This work was supported by the National Institutes of Health (grant numbers R01 CA189184, U01 CA206110, 2P30CA015704-40 [Gilliland]), the Matthias Lackas-Foundation, the German Consortium for Translational Cancer Research, and the EU TRANSCAN initiative. Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO): Funding for GECCO was provided by the National Cancer Institute, National Institutes of Health, US Department of Health and Human Services (grant numbers U01 CA137088, R01 CA059045, U01 CA164930). The Colon Cancer Family Registry (CFR) Illumina GWAS was supported by funding from the National Cancer Institute, National Institutes of Health (grant numbers U01 CA122839, R01 CA143247). The Colon CFR/CORECT Affymetrix Axiom GWAS and OncoArray GWAS were supported by funding from National Cancer Institute, National Institutes of Health (grant number U19 CA148107 to S. Gruber). The Colon CFR participant recruitment and collection of data and biospeci-mens used in this study were supported by the National Cancer Institute, National Institutes of Health (grant number UM1 CA167551), and through cooperative agreements with the following Colon CFR centers: Australasian Colorectal Cancer Family Registry (NCI/NIH grant numbers U01 CA074778 and U01/U24 CA097735), USC Consortium Colorectal Cancer Family Registry (NCI/NIH grant numbers U01/U24 CA074799), Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (NCI/NIH grant number U01/U24 CA074800), Ontario Familial Colorectal Cancer Registry (NCI/NIH grant number U01/U24 CA074783), Seattle Colorectal Cancer Family Registry (NCI/NIH grant number
U01/U24 CA074794), and University of Hawaii Colorectal Cancer Family Registry (NCI/NIH grant number U01/U24 CA074806). Additional support for case ascertainment was provided from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute to Fred Hutchinson Cancer Research Center (Control Nos. N01-CN-67009 and N01-PC-35142, and Contract No. HHSN2612013000121), the Hawai‘i Department of Health (Control Nos. N01-PC-67001 and N01-PC-35137 and Contract No. HHSN26120100037C), and the California Department of Public Health (contracts HHSN261201000035C awarded to the University of Southern California), and the following state cancer registries: AZ, CO, MN, NC, NH; and by the Victoria Cancer Registry and Ontario Cancer Registry. ESTHER/VERDI was supported by grants from the Baden-Württemberg Ministry of Science, Research and Arts and the German Cancer Aid. GALicia Estudio Oncológico de coloN (GALEON): FIS Intrasalud (PI13/01136). Melbourne Collaborative Cohort Study (MCCS) cohort recruitment was funded by VicHealth and Cancer Council Victoria. The MCCS was further supported by Australian NHMRC grants 509348, 209057, 251553, and 504711 and by infrastructure provided by Cancer Council Victoria. Cases and their vital status were ascertained through the Victorian Cancer Registry (VCR) and the Australian Institute of Health and Welfare (AIHW), including the National Death Index and the Australian Cancer Database. Memorial Sloan Kettering Cancer Center (MSKCC): The work at Sloan Kettering in New York was supported by the Robert and Kate Niehaus Center for Inherited Cancer Genomics and the Romeo Milio Foundation. Moffitt: This work was supported by funding from the National Institutes of Health (grant numbers R01 CA189184, P30 CA076292), Florida Department of Health Bankhead-Coley Grant 09BN-13, and the University of South Florida Oehler Foundation. Moffitt contributions were supported in part by the Total Cancer Care Initiative, Collaborative Data Services Core, and Tissue Core at the H. Lee Moffitt Cancer Center and Research Institute, a National Cancer Institute–designated Comprehensive Cancer Center (grant number P30 CA076292). Studies of Epidemiology and Risk Factors in Cancer Heredity: Cancer Research UK (C490/A16561). The Spanish study was supported by Instituto de Salud Carlos III, co-funded by FEDER funds: a way to build Europe (grants PI14-613 and PI09-1286), Catalan Government DURSI (grant 2014SGR647), and Junta de Castilla y León (grant LE22A10-2). The Swedish Low-risk Colorectal Cancer Study: The study was supported by grants from the Swedish Research Council (K2015-55X-22674-01-4, K2008-55X-20157-03-3, K2006-72X-20157-01-2) and the Stockholm County Council (ALF project). Research and contributions in Taiwan and Taipei Medical University were funded by Taiwan Ministry of Health and Wealth (MOHW105). Center for Inherited Disease Research (CIDR) genotyping for the Oncoarray was conducted under contract 268201200008I (to K. Doheny), through grant 101HG007491-01 (to C. I. Amos). The Norris Cotton Cancer Center (P30CA023108), The Quantitative Biology Research Institute (P20GM103534), and the Coordinating Center for Screen Detected Lesions (U01CA196386) also supported the efforts of C. I. Amos. This work was also supported by the National Cancer Institute (grant numbers U01 CA1817700, R01 CA144040). French Association Study Evaluating RISK for sporadic colorectal cancer (ASTERISK) was supported by the Hospital Clinical Research Program (PHRC), the Regional Council of Pays de la Loire, the Groupement des Entreprises Franc¸aises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Génétique, and the Ligue Régionale Contre le Cancer (LRCC). Hawai’i Colorectal Cancer Studies 2 & 3 (COLO2&3): National Institutes of Health (grant number R01 CA060987). Darmkrebs: Chancen der Verhütung durch Screening Study (DACHS): 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). Diet, Activity, and Lifestyle Study (DALS): National Institutes of Health (grant number R01 CA048998 to MLS). Health Professionals Follow-Up Study (HPFS) is supported by the National Institutes of Health (grant numbers P01 CA055075, UM1 CA167552, R01 137178, and P50 CA127003), Nurses’ Health Study (NHS) by the National Institutes of Health (grant numbers UM1 CA186107, R01 CA137178, P01 CA087969, and P50 CA127003), NHS II by the National Institutes of Health (grant numbers R01 050385CA and UM1 CA176726), and Physicians’ Health Study (PHS) by the National Institutes of Health (grant number R01 CA042182). Multiethnic Cohort Study (MEC): National Institutes of Health (grant numbers R37 CA054281, P01 CA033619, and R01 CA063464). Ontario Familial Colorectal Cancer Registry (OFCCR): National Institutes of Health, through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (grant number U01 CA074783; see Colon CFR section above). As a subset of ARCTIC, OFCCR is supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. Thomas J. Hudson and Brent W. Zanke are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO): Intramural Research Program of the Division of Cancer Epidemiology and Genetics and contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, Department of Health and Human Services. Additionally, a subset of control samples was genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS (35), Colon CGEMS pancreatic cancer scan (PanScan) (36,37), and the Lung Cancer and Smoking study (38). The prostate and PanScan study data sets were accessed with appropriate approval through the dbGaP on-line resource (http://cgems.cancer.gov/data/) accession numbers phs000207.v1.p1 and phs000206.v3.p2, respectively, and the lung data sets were accessed from the dbGaP website (http://www.ncbi.nlm.nih.gov/gap) through accession number phs000093.v2.p2. Funding for the Lung Cancer and Smoking study was provided by the NIH and the Genes, Environment and Health Initiative (GEI; Z01 CP 010200, NIH U01 HG004446, and NIH GEI U01 HG 004438). For the lung study, the GENEVA Coordinating Center provided assistance with genotype cleaning and general study coordination (23), and the Johns Hopkins University Center for Inherited
We thank Alina Hoehn for her valuable contributions to table/figure generation and organization of this manuscript. We are incredibly grateful for the contributions of Dr. Brian Henderson and Dr. Roger Green over the course of this study and acknowledge them in memoriam. We are also grateful for support from Daniel and Maryann Fong.
Disease Research conducted genotyping. Postmenopausal Hormones Supplementary Study to the Colon Cancer Family Registry (PMH): National Institutes of Health (grant number R01 CA076366). VITamins And Lifestyle (VITAL): National Institutes of Health (grant number K05 CA154337). Womens Health Initiative (WHI): The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, and US Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Colorectal Cancer: Longitudinal Observational study on Nutritional and lifestyle factors that influence colorectal tumor recurrence, survival and quality of life (COLON): The COLON study is sponsored by Wereld Kanker Onderzoek Fonds, including funds from grant 2014/1179 as part of the World Cancer Research Fund International Regular Grant Programme, by Alpe d’Huzes and the Dutch Cancer Society (UM 2012–5653, UW 2013-5927, UW2015-7946), and by TRANSCAN (JTC2012-MetaboCCC, JTC2013-FOCUS). Nutrition Questionnaires plus study (NQplus): The NQplus study is sponsored by a ZonMW investment grant (98-10030); by PREVIEW, the project PREVention of diabetes through lifestyle intervention and population studies in Europe and around the World (PREVIEW) project, which received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under grant No. 312057; by funds from TI Food and Nutrition (cardiovascular health theme), a public–private partnership on precompetitive research in food and nutrition, and by FOODBALL, the Food Biomarker Alliance, a project from JPI Healthy Diet for a Healthy Life. Asia Colorectal Cancer Consortium (ACCC): The work at Vanderbilt University School of Medicine was supported partly by US National Institutes of Health (grant numbers R37 CA070867, R01 CA182910, R01 CA148667) and Anne Potter Wilson funds from Vanderbilt University School of Medicine. Participating studies (grant support) in ACCC are: Shanghai Women’s Health Study (grant numbers R37 CA070867 and UM1CA182910), Shanghai Men’s Health Study (grant number UM1CA173640), Shanghai Colorectal Cancer Study 3 (NIH, grant numbers R37CA070867 and R01CA188214, and Ingram Professorship funds), Guangzhou Colorectal Cancer Study (National Key Scientific and Technological Project, 2011ZX09307-001-04), the Japan BioBank Colorectal Cancer Study (grant from the Ministry of Education, Culture, Sports, Science and Technology of the Japanese government), the Hwasun Cancer Epidemiology Study–Colon and Rectum Cancer (HCES-CRC; grants from Chonnam National University Hwasun Hospital, HCRI15011-1), Aichi Colorectal Cancer Study (Grant-in-aid for Cancer Research, Grant for the Third Term Comprehensive Control Research for Cancer and Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Nos. 17015018 and 221S0001), and Korean Cancer Prevention Study-II (KCPS-II) Colorectal Cancer Study (National R&D Program for cancer control, 1220180; Seoul R&D Program, 10526). US-Japan Colorectal Cancer GWAS: The colorectal cancer GWAS among Japanese was funded through the NIH (grant numbers R01 CA126895, R01 CA104132, U24 CA074806). Genotyping of the additional MEC controls was funded through the National Institutes of Health (grant numbers R01 CA132839, U01 HG004726). MEC was funded through the National Institutes of Health (grant numbers R37 CA054281, P01 CA033619, R01 CA063464). Japan Public Health Center-based Prospective Study (JPHC) was supported by the National Cancer Center Research and Development Fund (since 2011) and a Grant-in-Aid for Cancer Research (from 1989 to 2010) from the Ministry of Health, Labor and Welfare of Japan. The Fukuoka Colorectal Cancer Study was funded by the Ministry of Education, Culture, Sports, Science and Technology, Japan. Hispanic Colorectal Cancer GWAS: This work was supported by the National Institutes of Health (grant numbers R01 CA155101, U01 HG004726, R01 CA140561, T32 ES013678, U19 CA148107, P30 CA014089). The US-Japan Colorectal Cancer GWAS and the African American Colorectal Cancer GWAS were funded through the US National Institutes of Health (grant numbers 1R01-CA126895, 1R01-CA126895-S1, 1R01-CA104132, 2U24-CA074806). The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health. Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI/SAIC-Frederick, Inc. (SAIC-F) subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through an SAIC-F subcontract to Van Andel Institute (10ST1035). Additional data repository and project management were provided by SAIC-F (HHSN261200800001E). The Brain Bank was supported by a supplement to University of Miami (grants DA006227 and DA033684) and to contract N01MH000028. Statistical Methods development grants were made to the University of Geneva (MH090941 and MH101814), the University of Chicago (MH090951, MH090937, MH101820, MH101825), the University of North Carolina - Chapel Hill (MH090936 and MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University St Louis (MH101810), and the University of Pennsylvania (MH101822). The data used for the analyses described in this manuscript were obtained from the GTEx Portal on October 19, 2016.
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