BACKGROUND: Risk variants identified so far for colorectal cancer explain only a small proportion of familial risk of this cancer, particularly in Asians. METHODS: We performed a genome-wide association study (GWAS) of colorectal cancer in East Asians, including 23,572 colorectal cancer cases and 48,700 controls. To identify novel risk loci, we selected 60 promising risk variants for replication using data from 58,131 colorectal cancer cases and 67,347 controls of European descent. To identify additional risk variants in known colorectal cancer loci, we performed conditional analyses in East Asians. RESULTS: An indel variant, rs67052019 at 1p13.3, was found to be associated with colorectal cancer risk at P = 3.9 × 10-8 in Asians (OR per allele deletion = 1.13, 95% confidence interval = 1.08-1.18). This association was replicated in European descendants using a variant (rs2938616) in complete linkage disequilibrium with rs67052019 (P = 7.7 × 10-3). Of the remaining 59 variants, 12 showed an association at P < 0.05 in the European-ancestry study, including rs11108175 and rs9634162 at P < 5 × 10-8 and two variants with an association near the genome-wide significance level (rs60911071, P = 5.8 × 10-8; rs62558833, P = 7.5 × 10-8) in the combined analyses of Asian- and European-ancestry data. In addition, using data from East Asians, we identified 13 new risk variants at 11 loci reported from previous GWAS. CONCLUSIONS: In this large GWAS, we identified three novel risk loci and two highly suggestive loci for colorectal cancer risk and provided evidence for potential roles of multiple genes and pathways in the etiology of colorectal cancer. In addition, we showed that additional risk variants exist in many colorectal cancer risk loci identified previously. IMPACT: Our study provides novel data to improve the understanding of the genetic basis for colorectal cancer risk.

Broad Institute of Harvard and MIT Cambridge Massachusetts

Cancer Prevention and Control Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona Spain

Case Comprehensive Cancer Center Case Western Reserve University Cleveland Ohio

Center for Colorectal Cancer National Cancer Center Hospital National Cancer Center Gyeonggi do South Korea

Channing Division of Network Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts

CIBER Epidemiología y Salud Pública Madrid Spain

Clinical Genetics Service Department of Medicine Memorial Sloan Kettering Cancer Center New York New York

Department of Biostatistics University of Washington Seattle Washington

Department of Cancer Biomedical Science Graduate School of Cancer Science and Policy National Cancer Center Gyeonggi do South Korea

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Department of Epidemiology and Health Promotion Graduate School of Public Health Yonsei University Seoul Korea

Department of Epidemiology and Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University Boston Massachusetts

Department of Epidemiology Nagoya University Graduate School of Medicine Nagoya Japan

Department of Epidemiology University of Washington Seattle Washington

Department of Medicine 1 University Hospital Dresden Technische Universität Dresden Dresden Germany

Department of Medicine Weill Cornell Medical College New York New York

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Molecular Physiology and Biophysics Vanderbilt University School of Medicine Nashville Tennessee

Department of Preventive Medicine Chonnam National University Medical School Gwangju South Korea

Department of Preventive Medicine Seoul National University College of Medicine Seoul National University Cancer Research Institute Seoul Korea

Department of Preventive Medicine Seoul National University College of Medicine Seoul South Korea

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Department of Social and Preventive Medicine Hallym University College of Medicine Okcheon dong Korea

Division of Cancer Epidemiology and Genetics National Cancer Institute NIH Bethesda Maryland

Division of Epidemiology Department of Medicine Vanderbilt Ingram Cancer Center Vanderbilt Epidemiology Center Vanderbilt University School of Medicine Nashville Tennessee

Division of Gastroenterology and Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Massachusetts

Division of Human Nutrition Wageningen University and Research Wageningen the Netherlands

Division of Molecular and Clinical Epidemiology Aichi Cancer Center Research Institute Nagoya Japan

Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

General Surgery Department Tangdu Hospital 4th Military Medical University Xi'an Shaanxi China

Institute for Health Promotion Graduate School of Public Health Yonsei University Seoul Korea

Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague Czech Republic

Institute of Cancer Research Department of Medicine 1 Medical University Vienna Vienna Austria

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Jeonnam Regional Cancer Center Chonnam National University Hwasun Hospital Hwasun South Korea

Kyoto McGill International Collaborative School in Genomic Medicine Kyoto University Graduate School of Medicine Kyoto Japan

Laboratory for Statistical Analysis RIKEN Center for Integrative Medical Sciences Kanagawa Japan

Laboratory of Clinical Genome Sequencing Department of Computational Biology and Medical Sciences Graduate School of Frontier Sciences University of Tokyo Tokyo Japan

Laboratory of Genome Technology Human Genome Center Institute of Medical Science University of Tokyo Tokyo Japan

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

School of Public Health Sun Yat sen University Guangzhou China

School of Public Health University of Washington Seattle Washington

State Key Laboratory of Oncogene and Related Genes and Department of Epidemiology Shanghai Cancer Institute Renji Hospital Shanghai Jiaotong University School of Medicine Shanghai China

State Key Laboratory of Oncology in South China Cancer Center Sun Yat sen University Guangzhou China

University of Hawaii Cancer Center Honolulu Hawaii

University of Southern California Preventative Medicine Los Angeles California

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Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes

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Genome-wide Interaction Study with Smoking for Colorectal Cancer Risk Identifies Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune Response