Discovery of common and rare genetic risk variants for colorectal cancer.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA. Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA. Biomedical Informatics Program, Stanford University, Stanford, CA, USA. Department of Computer Science, Stanford University, Stanford, CA, USA. Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA. Department of Genome Sciences, University of Washington, Seattle, WA, USA. Department of Biostatistics, University of Washington, Seattle, WA, USA. Department of Genetics, Stanford University, Stanford, CA, USA. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain. CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA. Gastroenterology Department, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. Hellenic Health Foundation, Athens, Greece. 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. Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA. Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France. Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK. Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA. Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria. Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany. Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia. University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria, Australia. Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia. Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA. Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA. Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA. Department of Epidemiology, University of Washington, Seattle, WA, USA. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Broad Institute of Harvard and MIT, Cambridge, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Cancer Epidemiology Group, University Medical Centre Hamburg-Eppendorf, University Cancer Centre Hamburg (UCCH), Hamburg, Germany. Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain. Department of Hematology-Oncology, Chonnam National University Hospital, Hwasun, South Korea. Department of Epidemiology and Biostatistics, Imperial College London, London, UK. Department of Surgery and Cancer, Imperial College London, London, UK. Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA. Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ, USA. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia. Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands. Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia. International Agency for Research on Cancer, World Health Organization, Lyon, France. Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA. SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. University of Hawaii Cancer Research Center, Honolulu, HI, USA. Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France. Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA. Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA. Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden. Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA. Department of Epidemiology, School of Public Health and Institute of Health and Environment, Seoul National University, Seoul, South Korea. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. Nuffield Department of Population Health, University of Oxford, Oxford, UK. Gastroenterology Department, Bellvitge University Hospital, L'Hospitalet de Llobregat, Barcelona, Spain. Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA. Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA. Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK. Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea. Office of Public Health Studies, University of Hawaii Manoa, Honolulu, HI, USA. Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea. Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. The Clalit Health Services, Personalized Genomic Service, Carmel, Haifa, Israel. Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel. Clalit National Cancer Control Center, Haifa, Israel. Center for Community Health Integration and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA. Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden. Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA. Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, Cleveland, OH, USA. Biomedicine Institute (IBIOMED), University of León, León, Spain. Cancer Risk Factors and Life-Style Epidemiology Unit, Institute of Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy. USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA. Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic. Italian Institute for Genomic Medicine (IIGM), Turin, Italy. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Department of Medicine, Weill Cornell Medical College, New York, NY, USA. Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA, USA. Department of Medical Sciences, University of Turin, Turin, Italy. The Clinical Epidemiology Unit, Memorial University Medical School, Newfoundland, Canada. Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France. CESP (Inserm U1018), Facultés de Medicine Université Paris-Sud, UVSQ, Université Paris-Saclay, Gustave Roussy, Villejuif, France. Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA. Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. School of Public Health, Imperial College London, London, UK. Escuela Andaluza de Salud Pública. Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Universidad de Granada, Granada, Spain. Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA. Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Oncology Unit, Hillel Yaffe Medical Center, Hadera, Israel. Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA. Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Saarland Cancer Registry, Saarbrücken, Germany. Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA. National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic. Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic. Medical Faculty, University of Heidelberg, Heidelberg, Germany. School of Medicine, University of Dundee, Dundee, Scotland, UK. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden. Memorial University of Newfoundland, Discipline of Genetics, St. John's, Newfoundland, Canada. Division of Hematology, University of Toronto, Toronto, Ontario, Canada. Genomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA. Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. upeters@fredhutch.org. Department of Epidemiology, University of Washington, Seattle, WA, USA. upeters@fredhutch.org.

Nature genetics. 2019;(1):76-87

Abstract

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.

Methodological quality

Publication Type : Meta-Analysis

Metadata