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    Nature genetics. 2018 Dec 3. doi: 10.1038/s41588-018-0286-6. pii: 10.1038/s41588-018-0286-6
    Discovery of common and rare genetic risk variants for colorectal cancer.
    Huyghe JR1,  Bien SA2,  Harrison TA3,  Kang HM4,  Chen S5,  Schmit SL6,  Conti DV7,  Qu C8,  Jeon J9,  Edlund CK10,  Greenside P11,  Wainberg M12,  Schumacher FR13,  Smith JD14,  Levine DM15,  Nelson SC16,  Sinnott-Armstrong NA17,  Albanes D18,  Alonso MH19,  Anderson K20,  Arnau-Collell C21,  Arndt V22,  Bamia C23,  Banbury BL24,  Baron JA25,  Berndt SI26,  Bézieau S27,  Bishop DT28,  Boehm J29,  Boeing H30,  Brenner H31,  Brezina S32,  Buch S33,  Buchanan DD34,  Burnett-Hartman A35,  Butterbach K36,  Caan BJ37,  Campbell PT38,  Carlson CS39,  Castellví-Bel S40,  Chan AT41,  Chang-Claude J42,  Chanock SJ43,  Chirlaque MD44,  Cho SH45,  Connolly CM46,  Cross AJ47,  Cuk K48,  Curtis KR49,  de la Chapelle A50,  Doheny KF51,  Duggan D52,  Easton DF53,  Elias SG54,  Elliott F55,  English DR56,  Feskens EJM57,  Figueiredo JC58,  Fischer R59,  FitzGerald LM60,  Forman D61,  Gala M62,  Gallinger S63,  Gauderman WJ64,  Giles GG65,  Gillanders E66,  Gong J67,  Goodman PJ68,  Grady WM69,  Grove JS70,  Gsur A71,  Gunter MJ72,  Haile RW73,  Hampe J74,  Hampel H75,  Harlid S76,  Hayes RB77,  Hofer P78,  Hoffmeister M79,  Hopper JL80,  Hsu WL81,  Huang WY82,  Hudson TJ83,  Hunter DJ84,  Ibañez-Sanz G85,  Idos GE86,  Ingersoll R87,  Jackson RD88,  Jacobs EJ89,  Jenkins MA90,  Joshi AD91,  Joshu CE92,  Keku TO93,  Key TJ94,  Kim HR95,  Kobayashi E96,  Kolonel LN97,  Kooperberg C98,  Kühn T99,  Küry S100,  Kweon SS101,  Larsson SC102,  Laurie CA103,  Le Marchand L104,  Leal SM105,  Lee SC106,  Lejbkowicz F107,  Lemire M108,  Li CI109,  Li L110,  Lieb W111,  Lin Y112,  Lindblom A113,  Lindor NM114,  Ling H115,  Louie TL116,  Männistö S117,  Markowitz SD118,  Martín V119,  Masala G120,  McNeil CE121,  Melas M122,  Milne RL123,  Moreno L124,  Murphy N125,  Myte R126,  Naccarati A127,  Newcomb PA128,  Offit K129,  Ogino S130,  Onland-Moret NC131,  Pardini B132,  Parfrey PS133,  Pearlman R134,  Perduca V135,  Pharoah PDP136,  Pinchev M137,  Platz EA138,  Prentice RL139,  Pugh E140,  Raskin L141,  Rennert G142,  Rennert HS143,  Riboli E144,  Rodríguez-Barranco M145,  Romm J146,  Sakoda LC147,  Schafmayer C148,  Schoen RE149,  Seminara D150,  Shah M151,  Shelford T152,  Shin MH153,  Shulman K154,  Sieri S155,  Slattery ML156,  Southey MC157,  Stadler ZK158,  Stegmaier C159,  Su YR160,  Tangen CM161,  Thibodeau SN162,  Thomas DC163,  Thomas SS164,  Toland AE165,  Trichopoulou A166,  Ulrich CM167,  Van Den Berg DJ168,  van Duijnhoven FJB169,  Van Guelpen B170,  van Kranen H171,  Vijai J172,  Visvanathan K173,  Vodicka P174,  Vodickova L175,  Vymetalkova V176,  Weigl K177,  Weinstein SJ178,  White E179,  Win AK180,  Wolf CR181,  Wolk A182,  Woods MO183,  Wu AH184,  Zaidi SH185,  Zanke BW186,  Zhang Q187,  Zheng W188,  Scacheri PC189,  Potter JD190,  Bassik MC191,  Kundaje A192,  Casey G193,  Moreno V194,  Abecasis GR195,  Nickerson DA196,  Gruber SB197,  Hsu L198,  Peters U199
    Author information
    1Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    2Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    3Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    4Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
    5Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
    6Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
    7Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    8Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    9Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA.
    10Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    11Biomedical Informatics Program, Stanford University, Stanford, CA, USA.
    12Department of Computer Science, Stanford University, Stanford, CA, USA.
    13Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
    14Department of Genome Sciences, University of Washington, Seattle, WA, USA.
    15Department of Biostatistics, University of Washington, Seattle, WA, USA.
    16Department of Biostatistics, University of Washington, Seattle, WA, USA.
    17Department of Genetics, Stanford University, Stanford, CA, USA.
    18Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    19Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
    20Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, USA.
    21Gastroenterology 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.
    22Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    23Hellenic Health Foundation, Athens, Greece.
    24Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    25Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
    26Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    27Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
    28Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
    29Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
    30Department of Epidemiology, German Institute of Human Nutrition (DIfE), Potsdam-Rehbrücke, Germany.
    31Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    32Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
    33Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
    34Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
    35Institute for Health Research, Kaiser Permanente Colorado, Denver, CO, USA.
    36Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    37Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA, USA.
    38Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
    39Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    40Gastroenterology 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.
    41Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
    42Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    43Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    44CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
    45Department of Hematology-Oncology, Chonnam National University Hospital, Hwasun, South Korea.
    46Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    47Department of Epidemiology and Biostatistics, Imperial College London, London, UK.
    48Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    49Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    50Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
    51Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
    52Translational Genomics Research Institute - An Affiliate of City of Hope, Phoenix, AZ, USA.
    53Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    54Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
    55Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
    56Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
    57Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands.
    58Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
    59University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
    60Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
    61International Agency for Research on Cancer, World Health Organization, Lyon, France.
    62Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
    63Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
    64Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    65Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
    66Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
    67Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    68SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    69Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    70University of Hawaii Cancer Research Center, Honolulu, HI, USA.
    71Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
    72Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    73Division of Oncology, Department of Medicine, Stanford University, Stanford, CA, USA.
    74Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany.
    75Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
    76Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
    77Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA.
    78Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Vienna, Austria.
    79Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    80Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
    81Department of Biostatistics, University of Washington, Seattle, WA, USA.
    82Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    83Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
    84Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
    85Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
    86Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    87Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
    88Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH, USA.
    89Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
    90Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
    91Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
    92Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
    93Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
    94Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK.
    95Department of Surgery, Chonnam National University Hwasun Hospital and Medical School, Hwasun, Korea.
    96Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    97Office of Public Health Studies, University of Hawaii Manoa, Honolulu, HI, USA.
    98Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    99Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    100Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France.
    101Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
    102Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    103Department of Biostatistics, University of Washington, Seattle, WA, USA.
    104University of Hawaii Cancer Research Center, Honolulu, HI, USA.
    105Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
    106Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
    107The Clalit Health Services, Personalized Genomic Service, Carmel, Haifa, Israel.
    108Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
    109Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    110Center for Community Health Integration and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
    111Institute of Epidemiology, PopGen Biobank, Christian-Albrechts-University Kiel, Kiel, Germany.
    112Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    113Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
    114Department of Health Science Research, Mayo Clinic, Scottsdale, AZ, USA.
    115Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
    116Department of Biostatistics, University of Washington, Seattle, WA, USA.
    117Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland.
    118Departments of Medicine and Genetics, Case Comprehensive Cancer Center, Case Western Reserve University, and University Hospitals of Cleveland, Cleveland, OH, USA.
    119CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
    120Cancer Risk Factors and Life-Style Epidemiology Unit, Institute of Cancer Research, Prevention and Clinical Network - ISPRO, Florence, Italy.
    121USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA.
    122Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    123Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
    124Gastroenterology 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.
    125Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
    126Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
    127Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
    128Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    129Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    130Broad Institute of Harvard and MIT, Cambridge, MA, USA.
    131Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.
    132Italian Institute for Genomic Medicine (IIGM), Turin, Italy.
    133The Clinical Epidemiology Unit, Memorial University Medical School, Newfoundland, Canada.
    134Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
    135Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, Paris, France.
    136Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    137Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
    138Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
    139Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    140Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
    141Division of Epidemiology, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
    142Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
    143Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
    144School of Public Health, Imperial College London, London, UK.
    145CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
    146Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
    147Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    148Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
    149Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
    150Division of Cancer Control and Population Sciences, National Cancer Institute, Bethesda, MD, USA.
    151Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    152Center for Inherited Disease Research (CIDR), Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA.
    153Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
    154Oncology Unit, Hillel Yaffe Medical Center, Hadera, Israel.
    155Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
    156Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
    157Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Melbourne, Australia.
    158Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    159Saarland Cancer Registry, Saarbrücken, Germany.
    160Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    161SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    162Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
    163Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    164Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    165Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
    166Hellenic Health Foundation, Athens, Greece.
    167Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
    168Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    169Division of Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands.
    170Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
    171National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
    172Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    173Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
    174Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
    175Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
    176Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
    177Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    178Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    179Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    180Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Victoria, Australia.
    181School of Medicine, University of Dundee, Dundee, Scotland, UK.
    182Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    183Memorial University of Newfoundland, Discipline of Genetics, St. John's, Newfoundland, Canada.
    184Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    185Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
    186Division of Hematology, University of Toronto, Toronto, Ontario, Canada.
    187Genomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    188Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
    189Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA.
    190Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    191Department of Genetics, Stanford University, Stanford, CA, USA.
    192Department of Computer Science, Stanford University, Stanford, CA, USA.
    193Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
    194Cancer Prevention and Control Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
    195Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA.
    196Department of Genome Sciences, University of Washington, Seattle, WA, USA.
    197Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    198Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    199Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. upeters@fredhutch.org.
    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, 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.


    Publikations ID: 30510241
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