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

About this Publication
Title
Fine-mapping analysis including over 254,000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes.
Pubmed ID
38670944 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Nat Commun. 2024 Apr 26; Volume 15 (Issue 1): Pages 3557
Authors
Chen Z, Guo X, Tao R, Huyghe JR, Law PJ, Fernandez-Rozadilla C, Ping J, Jia G, Long J, Li C, Shen Q, Xie Y, Timofeeva MN, Thomas M, Schmit SL, Díez-Obrero V, Devall M, Moratalla-Navarro F, Fernandez-Tajes J, Palles C, ...show more Sherwood K, Briggs SEW, Svinti V, Donnelly K, Farrington SM, Blackmur J, Vaughan-Shaw PG, Shu XO, Lu Y, Broderick P, Studd J, Harrison TA, Conti DV, Schumacher FR, Melas M, Rennert G, Obón-Santacana M, Martín-Sánchez V, Oh JH, Kim J, Jee SH, Jung KJ, Kweon SS, Shin MH, Shin A, Ahn YO, Kim DH, Oze I, Wen W, Matsuo K, Matsuda K, Tanikawa C, Ren Z, Gao YT, Jia WH, Hopper JL, Jenkins MA, Win AK, Pai RK, Figueiredo JC, Haile RW, Gallinger S, Woods MO, Newcomb PA, Duggan D, Cheadle JP, Kaplan R, Kerr R, Kerr D, Kirac I, Böhm J, Mecklin JP, Jousilahti P, Knekt P, Aaltonen LA, Rissanen H, Pukkala E, Eriksson JG, Cajuso T, Hänninen U, Kondelin J, Palin K, Tanskanen T, Renkonen-Sinisalo L, Männistö S, Albanes D, Weinstein SJ, Ruiz-Narvaez E, Palmer JR, Buchanan DD, Platz EA, Visvanathan K, Ulrich CM, Siegel E, Brezina S, Gsur A, Campbell PT, Chang-Claude J, Hoffmeister M, Brenner H, Slattery ML, Potter JD, Tsilidis KK, Schulze MB, Gunter MJ, Murphy N, Castells A, Castellví-Bel S, Moreira L, Arndt V, Shcherbina A, Bishop DT, Giles GG, Southey MC, Idos GE, McDonnell KJ, Abu-Ful Z, Greenson JK, Shulman K, Lejbkowicz F, Offit K, Su YR, Steinfelder R, Keku TO, van Guelpen B, Hudson TJ, Hampel H, Pearlman R, Berndt SI, Hayes RB, Martinez ME, Thomas SS, Pharoah PDP, Larsson SC, Yen Y, Lenz HJ, White E, Li L, Doheny KF, Pugh E, Shelford T, Chan AT, Cruz-Correa M, Lindblom A, Hunter DJ, Joshi AD, Schafmayer C, Scacheri PC, Kundaje A, Schoen RE, Hampe J, Stadler ZK, Vodicka P, Vodickova L, Vymetalkova V, Edlund CK, Gauderman WJ, Shibata D, Toland A, Markowitz S, Kim A, Chanock SJ, van Duijnhoven F, Feskens EJM, Sakoda LC, Gago-Dominguez M, Wolk A, Pardini B, FitzGerald LM, Lee SC, Ogino S, Bien SA, Kooperberg C, Li CI, Lin Y, Prentice R, Qu C, Bézieau S, Yamaji T, Sawada N, Iwasaki M, Le Marchand L, Wu AH, Qu C, McNeil CE, Coetzee G, Hayward C, Deary IJ, Harris SE, Theodoratou E, Reid S, Walker M, Ooi LY, Lau KS, Zhao H, Hsu L, Cai Q, Dunlop MG, Gruber SB, Houlston RS, Moreno V, Casey G, Peters U, Tomlinson I, Zheng W
Affiliations
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.
  • Edinburgh Cancer Research Centre, Institute of Genomics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
  • Colon Cancer Genetics Group, Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Genomic Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.
  • Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute, Barcelona, Spain.
  • Center for Public Health Genomics, Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
...show more
  • Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • Department of Public Health, Richard Doll Building, University of Oxford, Oxford, UK.
  • Department of Preventive Medicine, USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA.
  • The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA.
  • Clalit National Cancer Control Center, Haifa, Israel.
  • Consortium for Biomedical Research in Epidemiology and Public Health, Madrid, Spain.
  • Center for Colorectal Cancer, National Cancer Center Hospital, National Cancer Center, Gyeonggi-do, South Korea.
  • Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, Gyeonggi-do, South Korea.
  • Department of Epidemiology and Health Promotion, Graduate School of Public Health, Yonsei University, Seoul, South Korea.
  • Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, South Korea.
  • Cancer Research Institute, Seoul National University, Seoul, South Korea.
  • Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, South Korea.
  • Department of Social and Preventive Medicine, Hallym University College of Medicine, Okcheon-dong, South Korea.
  • Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan.
  • Department of Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, 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.
  • School of Public Health, Sun Yat-sen University, Guangzhou, China.
  • 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.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, VIC, Australia.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA.
  • Division of Oncology, Department of Medicine, Cedars-Sinai Cancer Research Center for Health Equity, Los Angeles, CA, USA.
  • Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • Division of Biomedical Sciences, Memorial University of Newfoundland, St. John, ON, Canada.
  • City of Hope National Medical Center, Translational Genomics Research Institute, Phoenix, AZ, USA.
  • Institute of Medical Genetics, Cardiff University, Cardiff, UK.
  • MRC Clinical Trials Unit, Medical Research Council, Cardiff, UK.
  • Department of Oncology, University of Oxford, Oxford, UK.
  • Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • Department of Surgical Oncology, University Hospital for Tumors, Sestre milosrdnice University Hospital Center, Zagreb, Croatia.
  • Department of Pathology, Central Finland Health Care District, Jyväskylä, Finland.
  • Central Finland Health Care District, Jyväskylä, Finland.
  • Department of Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
  • Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland.
  • Department of Public Health and Welfare, Finnish Institute for Health and Welfare, Helsinki, Finland.
  • Faculty of Social Sciences, Tampere University, Tampere, Finland.
  • Folkhälsan Research Centre, University of Helsinki, Helsinki, Finland.
  • Department of Surgery, Abdominal Centre, Helsinki University Hospital, Helsinki, Finland.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
  • Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
  • Colorectal Oncogenomics Group, Department of Clinical Pathology, University of Melbourne, Parkville, VIC, Australia.
  • Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
  • Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA.
  • Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
  • Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
  • Department of Epidemiology and Population Health, Albert Einstein College of Medicine, New York, NY, USA.
  • Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.
  • Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA.
  • Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
  • Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France.
  • 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.
  • Department of Genetics, Stanford University, Stanford, CA, USA.
  • Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, VIC, Australia.
  • Department of Medical Oncology and Center For Precision Medicine, City of Hope National Medical Center, Duarte, CA, USA.
  • Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
  • Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
  • Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC, USA.
  • Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
  • Ontario Institute for Cancer Research, Toronto, ON, Canada.
  • Division of Human Genetics, Department of Internal Medicine, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
  • Division of Epidemiology, Department of Population Health, New York University School of Medicine, New York, NY, USA.
  • Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA, USA.
  • Fred Hutchinson Cancer Center, Seattle, WA, USA.
  • Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • Taipei Medical University, Taipei, Taiwan.
  • Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Center for Inherited Disease Research, Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Comprehensive Cancer Center, University of Puerto Rico, San Juan, Puerto Rico.
  • Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA.
  • Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 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 Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  • Department of Medicine I, University Hospital Dresden, Technische Universität Dresden, Dresden, Germany.
  • 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 Surgery, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 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 Human Nutrition and Health, Wageningen University and Research, Wageningen, The Netherlands.
  • Division of Human Nutrition, Wageningen University and Research, Wageningen, The Netherlands.
  • Genomic Medicine Group, Galician Public Foundation of Genomic Medicine, Servicio Galego de Saude, Santiago de Compostela, Spain.
  • Candiolo Cancer Institute FPO-IRCCS, Candiolo, (TO), Italy.
  • National University Cancer Institute, Singapore, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • Service de Génétique Médicale, Centre Hospitalier Universitaire Nantes, Nantes, France.
  • Division of Epidemiology, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan.
  • Division of Cohort Research, National Cancer Center Institute for Cancer Control, National Cancer Center, Tokyo, Japan.
  • Cancer Center, University of Hawaii, Honolulu, HI, USA.
  • Preventative Medicine, University of Southern California, Los Angeles, CA, USA.
  • 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.
  • MRC Human Genetics Unit, Institute of Genomics and Cancer, University of Edinburgh, Edinburgh, UK.
  • Lothian Birth Cohorts group, Department of Psychology, University of Edinburgh, Edinburgh, UK.
  • Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, UK.
  • Epithelial Biology Center and Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University Medical Center, Nashville, TN, USA. wei.zheng@vanderbilt.edu.
Abstract

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.

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