Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.

Biomedicine Institute University of León León Spain

Broad Institute of Harvard and MIT Cambridge MA USA

Broad Institute of MIT and Harvard Cambridge MA USA

Cancer Center University of Hawaii Honolulu HI USA

Cancer Epidemiology Division Cancer Council Victoria Melbourne VIC Australia

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

Cancer Immunology Program Dana Farber Harvard Cancer Center Boston MA USA

Cancer Research Institute Seoul National University Seoul South Korea

Candiolo Cancer Institute FPO IRCCS Candiolo Italy

Case Comprehensive Cancer Center Case Western Reserve University Cleveland OH USA

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

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

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

Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville VA USA

Central Finland Health Care District Jyväskylä Finland

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

Centre for Global Health Usher Institute University of Edinburgh Edinburgh UK

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

City of Hope National Medical Center Translational Genomics Research Institute Phoenix AZ USA

Clalit Health Services Personalized Genomic Service Lady Davis Carmel Medical Center Haifa Israel

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

Colon Cancer Genetics Group Medical Research Council Human Genetics Unit Institute of Genetics and Cancer University of Edinburgh Edinburgh UK

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute Barcelona Spain

Colorectal Oncogenomics Group Department of Clinical Pathology University of Melbourne Parkville VIC Australia

Comprehensive Cancer Center University of Puerto Rico San Juan Puerto Rico

Consortium for Biomedical Research in Epidemiology and Public Health Madrid Spain

Danish Institute for Advanced Study Department of Public Health University of Southern Denmark Odense Denmark

Department of Biomedical Informatics Vanderbilt University School of Medicine Nashville TN USA

Department of Biostatistics School of Public Health University of Washington Seattle WA USA

Department of Biostatistics University of Washington Seattle WA USA

Department of Biostatistics Vanderbilt University Medical Center Nashville TN USA

Department of Biostatistics Yale School of Public Health New Haven CT USA

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 Pathology University of Melbourne Melbourne VIC Australia

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 School of Public Health Imperial College London London UK

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

Department of Epidemiology and Population Health Albert Einstein College of Medicine New York NY USA

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 Baltimore MD USA

Department of Epidemiology Nagoya University Graduate School of Medicine Nagoya Japan

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

Department of Epidemiology University of Washington School of Public Health Seattle WA USA

Department of Epidemiology University of Washington Seattle WA USA

Department of Family Medicine and Public Health University of California San Diego La Jolla CA USA

Department of General Surgery University Hospital Rostock Rostock Germany

Department of Genetics and Genome Sciences Case Western Reserve University Cleveland OH USA

Department of Genetics Stanford University Stanford CA USA

Department of Genetics Yale School of Medicine New Haven CT USA

Department of Health and Welfare Finnish Institute for Health and Welfare Helsinki Finland

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

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 Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale AZ USA

Department of Medical and Clinical Genetics University of Helsinki Helsinki Finland

Department of Medical Oncology and Center For Precision Medicine City of Hope National Medical Center Duarte CA USA

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 Boston University School of Medicine Boston MA USA

Department of Medicine Keck School of Medicine University of Southern California Los Angeles CA 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 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 Epidemiology German Institute of Human Nutrition Potsdam Rehbruecke Nuthetal Germany

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

Department of Nutritional Sciences School of Public Health University of Michigan Ann Arbor MI USA

Department of Oncology University of Oxford Oxford UK

Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA USA

Department of Pathology Central Finland Health Care District Jyväskylä Finland

Department of Pathology National University Hospital National University Health System Singapore Singapore

Department of Pathology University of Michigan Ann Arbor MI 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 South Korea

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

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 and Welfare Finnish Institute for Health and Welfare Helsinki Finland

Department of Public Health Richard Doll Building University of Oxford Oxford UK

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

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

Department of Surgery Abdominal Centre Helsinki University Hospital Helsinki Finland

Department of Surgery University of Tennessee Health Science Center Memphis TN USA

Department of Surgical Oncology University Hospital for Tumors Sestre milosrdnice University Hospital Center Zagreb Croatia

Departments of Cancer Biology and Genetics and Internal Medicine Comprehensive Cancer Center 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 Biomedical Sciences Memorial University of Newfoundland St John ON Canada

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

Division of Cancer Epidemiology and Prevention Aichi Cancer Center Research Institute Nagoya Japan

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 Cohort Research National Cancer Center Institute for Cancer Control National Cancer Center Tokyo Japan

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

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

Division of Epidemiology National Cancer Center Institute for Cancer Control National Cancer Center Tokyo Japan

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

Division of Genetics and Epidemiology Institute of Cancer Research London UK

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

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

Division of Human Nutrition Wageningen University and Research Wageningen The Netherlands

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

Division of Oncology Department of Medicine Cedars Sinai Cancer Research Center for Health Equity Los Angeles CA USA

Division of Preventive Oncology German Cancer Research Center and National Center for Tumor Diseases Heidelberg Germany

Division of Research Kaiser Permanente Northern California Oakland CA USA

Edinburgh Cancer Research Centre Institute of Genomics and Cancer University of Edinburgh Edinburgh UK

Epithelial Biology Center and Department of Cell and Developmental Biology Vanderbilt University School of Medicine Nashville TN USA

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

Faculty of Social Sciences Tampere University Tampere Finland

Finnish Cancer Registry Institute for Statistical and Epidemiological Cancer Research Helsinki Finland

Folkhälsan Research Centre University of Helsinki Helsinki Finland

Fred Hutchinson Cancer Center Seattle WA USA

Gastroenterology Department Hospital Clínic Institut d'Investigacions Biomèdiques August Pi i Sunyer Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas University of Barcelona Barcelona Spain

Genome Scale Biology Research Program University of Helsinki Helsinki Finland

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

Genomic Medicine Group Galician Public Foundation of Genomic Medicine Servicio Galego de Saude Santiago de Compostela Spain

Genomic Medicine Group Instituto de Investigacion Sanitaria de Santiago Santiago de Compostela Spain

Genomic Medicine Institute Cleveland Clinic Cleveland OH USA

German Cancer Consortium German Cancer Research Center Heidelberg Germany

Human Potential Translational Research Programme National University of Singapore Singapore Singapore

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

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

Institute of Cancer and Genomic Sciences College of Medical and Dental Sciences University of Birmingham Birmingham UK

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

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Institute of Medical Genetics Cardiff University Cardiff UK

Institute of Nutritional Science University of Potsdam Potsdam Germany

Instituto de Investigación Sanitaria de Santiago de Compostela Santiago de Compostela Spain

Italian Institute for Genomic Medicine Candiolo Cancer Institute FPO IRCCS Candiolo Italy

Kaiser Permanente Washington Health Research Institute Seattle WA USA

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

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

Lothian Birth Cohorts group Department of Psychology University of Edinburgh Edinburgh UK

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

Menzies Institute for Medical Research University of Tasmania Hobart TAS Australia

MRC Clinical Trials Unit Medical Research Council Cardiff UK

MRC Human Genetics Unit Institute of Genomics and Cancer University of Edinburgh Edinburgh UK

National University Cancer Institute Singapore Cancer Science Institute of Singapore National University of Singapore Singapore Singapore

Nuffield Department of Population Health University of Oxford Oxford UK

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

Oncology Data Analytics Program Catalan Institute of Oncology Barcelona Spain

Ontario Institute for Cancer Research Toronto ON Canada

Population and Cancer Prevention Program Case Comprehensive Cancer Center Cleveland OH USA

Population Sciences Disparities and Community Engagement University of California San Diego Moores Cancer Center La Jolla CA USA

Precision Medicine School of Clinical Sciences at Monash Health Monash University Clayton VIC Australia

Preventative Medicine University of Southern California Los Angeles CA USA

Program in Computational Biology and Bioinformatics Yale University New Haven CT USA

Public Health Sciences Division Fred Hutchinson Cancer Center Seattle WA USA

Radcliffe Department of Medicine University of Oxford Oxford UK

Research Centre for Hauora and Health Massey University Wellington New Zealand

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

School of Public Health Sun Yat sen University Guangzhou China

School of Public Health University of Washington Seattle WA USA

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes France

Slone Epidemiology Center at Boston University Boston MA USA

State Key Laboratory of Oncogenes 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

Taipei Medical University Taipei Taiwan

The Steve and Cindy Rasmussen Institute for Genomic Medicine Nationwide Children's Hospital Columbus OH USA

Unit of General Practice and Primary Health Care University of Helsinki and Helsinki University Hospital Helsinki Finland

University Medical Centre Hamburg Eppendorf University Cancer Centre Hamburg Hamburg Germany

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

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

Van Andel Research Institute Grand Rapids MI USA

Vanderbilt Genetics Institute Vanderbilt University Medical Center Nashville 37232 TN USA

Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

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Search for germline gene variants in colorectal cancer families presenting with multiple primary colorectal cancers