To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta GA USA

Biomedical Informatics Program Stanford University Stanford CA USA

Biomedicine Institute University of León León Spain

Broad Institute of Harvard and MIT Cambridge MA USA

Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Victoria Australia

Cancer Epidemiology Group University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

Cancer Epidemiology Unit Nuffield Department of Population Health University of Oxford Oxford UK

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

Cancer Risk Factors and Life Style Epidemiology Unit Institute of Cancer Research Prevention and Clinical Network ISPRO Florence Italy

Cancer Science Institute of Singapore National University of Singapore Singapore Singapore

Center for Community Health Integration and Case Comprehensive Cancer Center Case Western Reserve University Cleveland OH USA

Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill NC USA

Center for Inherited Disease Research Institute of Genetic Medicine Johns Hopkins University Baltimore MD USA

Center for Public Health Genomics University of Virginia Charlottesville VA USA

Center for Statistical Genetics Department of Molecular and Human Genetics Baylor College of Medicine Houston TX USA

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

CESP Facultés de Medicine Université Paris Sud UVSQ Université Paris Saclay Gustave Roussy Villejuif France

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

CIBER de Epidemiología y Salud Pública Madrid Spain

Clalit National Cancer Control Center Haifa Israel

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston MA USA

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

Clinical Research Division Fred Hutchinson Cancer Research Center Seattle WA USA

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute IDIBELL Hospitalet de Llobregat Barcelona Spain

Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville Victoria Australia

Department of Biostatistics and Center for Statistical Genetics University of Michigan Ann Arbor MI USA

Department of Biostatistics University of Washington Seattle WA USA

Department of Cancer Biology and Genetics and the Comprehensive Cancer Center The Ohio State University Columbus OH USA

Department of Cancer Epidemiology H Lee Moffitt Cancer Center and Research Institute Tampa FL USA

Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden

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

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel

Department of Computer Science Stanford University Stanford CA USA

Department of Epidemiology and Biostatistics Imperial College London London UK

Department of Epidemiology German Institute of Human Nutrition Potsdam Rehbrücke Germany

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston MA USA

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Johns Hopkins University Baltimore MD USA

Department of Epidemiology Regional Health Council IMIB Arrixaca Murcia University Murcia Spain

Department of Epidemiology School of Public Health and Institute of Health and Environment Seoul National University Seoul South Korea

Department of Epidemiology University of Michigan Ann Arbor MI USA

Department of Epidemiology University of Washington Seattle WA USA

Department of General and Thoracic Surgery University Hospital Schleswig Holstein Campus Kiel Kiel Germany

Department of Genetics and Genome Sciences Case Western Reserve University School of Medicine Case Comprehensive Cancer Center Cleveland OH USA

Department of Genetics Stanford University Stanford CA USA

Department of Genome Sciences University of Washington Seattle WA USA

Department of Haematology Oncology National University Cancer Institute Singapore Singapore

Department of Health Science Research Mayo Clinic Scottsdale AZ USA

Department of Hematology Oncology Chonnam National University Hospital Hwasun South Korea

Department of Immunology and Infectious Diseases Harvard T H Chan School of Public Health Harvard University Boston MA USA

Department of Internal Medicine University of Utah Salt Lake City UT USA

Department of Medical Sciences University of Turin Turin Italy

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

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh PA USA

Department of Medicine Division of Endocrinology Diabetes and Metabolism The Ohio State University Columbus OH USA

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY USA

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles CA USA

Department of Medicine University of North Carolina School of Medicine Chapel Hill NC USA

Department of Medicine Weill Cornell Medical College New York NY USA

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 Oncologic Pathology Dana Farber Cancer Institute Boston MA USA

Department of Population and Quantitative Health Sciences Case Western Reserve University Cleveland OH USA

Department of Preventive Medicine Chonnam National University Medical School Gwangju Korea

Department of Preventive Medicine Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Preventive Medicine USC Norris Comprehensive Cancer Center Keck School of Medicine University of Southern California Los Angeles CA USA

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Public Health Solutions National Institute for Health and Welfare Helsinki Finland

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Department of Surgery and Cancer Imperial College London London UK

Department of Surgery Chonnam National University Hwasun Hospital and Medical School Hwasun Korea

Department of Surgical Sciences Uppsala University Uppsala Sweden

Departments of Cancer Biology and Genetics and Internal Medicine Comprehensive Cancer Center The Ohio State University Columbus OH USA

Departments of Medicine and Genetics Case Comprehensive Cancer Center Case Western Reserve University and University Hospitals of Cleveland Cleveland OH USA

Division of Cancer Control and Population Sciences National Cancer Institute Bethesda MD USA

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda MD USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Epidemiology and Community Health University of Minnesota Minneapolis MN USA

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

Division of Epidemiology Department of Population Health New York University School of Medicine New York NY USA

Division of Epidemiology Vanderbilt Epidemiology Center Vanderbilt University School of Medicine Nashville TN USA

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston MA USA

Division of Hematology University of Toronto Toronto Ontario Canada

Division of Human Genetics Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus OH USA

Division of Human Nutrition and Health Wageningen University and Research Wageningen The Netherlands

Division of Laboratory Genetics Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Division of Oncology Department of Medicine Stanford University Stanford CA USA

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Division of Research Kaiser Permanente Medical Care Program Oakland CA USA

Division of Research Kaiser Permanente Northern California Oakland CA USA

Epidemiology and Prevention Unit Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy

Escuela Andaluza de Salud Pública Instituto de Investigación Biosanitaria ibs GRANADA Hospitales Universitarios de Granada Universidad de Granada Granada Spain

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

Gastroenterology Department Bellvitge University Hospital L'Hospitalet de Llobregat Barcelona Spain

Gastroenterology Department Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer University of Barcelona Barcelona Spain

Genetic Epidemiology Laboratory Department of Pathology The University of Melbourne Melbourne Australia

Genomic Medicine and Family Cancer Clinic Royal Melbourne Hospital Parkville Victoria Australia

Genomics Shared Resource Fred Hutchinson Cancer Research Center Seattle WA USA

German Cancer Consortium Heidelberg Germany

Hellenic Health Foundation Athens Greece

Huntsman Cancer Institute and Department of Population Health Sciences University of Utah Salt Lake City UT USA

Institute for Health Research Kaiser Permanente Colorado Denver CO USA

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 of Vienna Vienna Austria

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Epidemiology PopGen Biobank Christian Albrechts University Kiel Kiel Germany

International Agency for Research on Cancer World Health Organization Lyon France

Italian Institute for Genomic Medicine Turin Italy

Jeonnam Regional Cancer Center Chonnam National University Hwasun Hospital Hwasun Korea

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht University Utrecht The Netherlands

Laboratoire de Mathématiques Appliquées MAP5 Université Paris Descartes Paris France

Leeds Institute of Medical Research at St James's University of Leeds Leeds UK

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto Ontario Canada

Medical Faculty University of Heidelberg Heidelberg Germany

Memorial University of Newfoundland Discipline of Genetics St John's Newfoundland Canada

Menzies Institute for Medical Research University of Tasmania Hobart Tasmania Australia

National Institute for Public Health and the Environment Bilthoven The Netherlands

Nuffield Department of Population Health University of Oxford Oxford UK

Nutrition and Metabolism Section International Agency for Research on Cancer World Health Organization Lyon France

Office of Public Health Studies University of Hawaii Manoa Honolulu HI USA

Oncology Unit Hillel Yaffe Medical Center Hadera Israel

Ontario Institute for Cancer Research Toronto Ontario Canada

Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA USA

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle WA USA

Ruth and Bruce Rappaport Faculty of Medicine Technion Israel Institute of Technology Haifa Israel

Saarland Cancer Registry Saarbrücken Germany

School of Medicine University of Dundee Dundee Scotland UK

School of Public Health Imperial College London London UK

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes France

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle WA USA

The Clalit Health Services Personalized Genomic Service Carmel Haifa Israel

The Clinical Epidemiology Unit Memorial University Medical School Newfoundland Canada

Translational Genomics Research Institute An Affiliate of City of Hope Phoenix AZ USA

University of Hawaii Cancer Research Center Honolulu HI USA

University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Parkville Victoria Australia

University of Michigan Comprehensive Cancer Center Ann Arbor MI USA

USC Norris Comprehensive Cancer Center University of Southern California Los Angeles CA USA

WHO Collaborating Center for Nutrition and Health Unit of Nutritional Epidemiology and Nutrition in Public Health Department of Hygiene Epidemiology and Medical Statistics School of Medicine National and Kapodistrian University of Athens Athens Greece

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Large-Scale Alternative Polyadenylation-Wide Association Studies to Identify Putative Cancer Susceptibility Genes

Genome-wide association studies and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer

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

Novel insights into genetic susceptibility for colorectal cancer from transcriptome-wide association and functional investigation

Combining Asian and European genome-wide association studies of colorectal cancer improves risk prediction across racial and ethnic populations

Elucidating the Risk of Colorectal Cancer for Variants in Hereditary Colorectal Cancer Genes

Probing the diabetes and colorectal cancer relationship using gene - environment interaction analyses

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Validation of a Genetic-Enhanced Risk Prediction Model for Colorectal Cancer in a Large Community-Based Cohort

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

Genetic Predictors for Fecal Propionate and Butyrate-Producing Microbiome Pathway Are Not Associated with Colorectal Cancer Risk: A Mendelian Randomization Analysis

Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries

Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis

Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region

Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study

Genetic architectures of proximal and distal colorectal cancer are partly distinct

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study

Two-Sample Mendelian Randomization Analysis of Associations Between Periodontal Disease and Risk of Cancer

Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts

Identifying Novel Susceptibility Genes for Colorectal Cancer Risk From a Transcriptome-Wide Association Study of 125,478 Subjects