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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Ceres Fernandez-Rozadilla - , Edinburgh Napier University (Author)
  • Maria Timofeeva - , Edinburgh Napier University (Author)
  • Zhishan Chen - , Vanderbilt University (Author)
  • Philip Law - , Children's Cancer Institute Australia Lowy Cancer Research Centre (Author)
  • Minta Thomas - , Fred Hutchinson Cancer Research Center (Author)
  • Stephanie Schmit - , Italian Institute for Genomic Medicine (IIGM) (Author)
  • Virginia Díez-Obrero - , Bellvitge Biomedical Research Institute (IDIBELL) (Author)
  • Li Hsu - , Fred Hutchinson Cancer Research Center (Author)
  • Juan Fernandez-Tajes - , Edinburgh Napier University (Author)
  • Claire Palles - , University College Birmingham (Author)
  • Kitty Sherwood - , Edinburgh Napier University (Author)
  • Sarah Briggs - , Oxford University Hospitals NHS Foundation Trust (Author)
  • Victoria Svinti - , Edinburgh Napier University (Author)
  • Kevin Donnelly - , Edinburgh Napier University (Author)
  • Susan Farrington - , Edinburgh Napier University (Author)
  • James Blackmur - , Edinburgh Napier University (Author)
  • Peter Vaughan-Shaw - , Edinburgh Napier University (Author)
  • Xiao-Ou Shu - , Vanderbilt University (Author)
  • Jirong Long - , Vanderbilt University (Author)
  • Qiuyin Cai - , Vanderbilt University (Author)
  • Xingyi Guo - , Vanderbilt University (Author)
  • Yingchang Lu - , Vanderbilt University (Author)
  • Peter Broderick - , Children's Cancer Institute Australia Lowy Cancer Research Centre (Author)
  • James Studd - , Children's Cancer Institute Australia Lowy Cancer Research Centre (Author)
  • Jeroen Huyghe - , Fred Hutchinson Cancer Research Center (Author)
  • Tabitha Harrison - , Fred Hutchinson Cancer Research Center (Author)
  • David Conti - , Southern California University of Health Sciences (Author)
  • Christopher Dampier - , West Virginia University (Author)
  • Mathew Devall - , West Virginia University (Author)
  • Fredrick Schumacher - , University Hospitals Cleveland Medical Center (Author)
  • Marilena Melas - , The Steve and Cindy Rasmussen Institute for Genomic Medicine (Author)
  • Gad Rennert - , Lady Davis Carmel Medical Center (Author)
  • Mireia Obón-Santacana - , Bellvitge Biomedical Research Institute (IDIBELL) (Author)
  • Vicente Martín-Sánchez - , Consortium for Biomedical Research in Epidemiology and Public Health (Author)
  • Ferran Moratalla-Navarro - , Bellvitge Biomedical Research Institute (IDIBELL) (Author)
  • Jae Hwan Oh - , National Cancer Center Japan (Author)
  • Jeongseon Kim - , Graduate School of Cancer Science and Policy (Author)
  • Sun Ha Jee - , Yonsei University Mirae Campus (Author)
  • Keum Ji Jung - , Yonsei University Mirae Campus (Author)
  • Sun-Seog Kweon - , Chonnam National University Medical School (Author)
  • Min-Ho Shin - , Chonnam National University Medical School (Author)
  • Aesun Shin - , Seoul National University College of Medicine (Author)
  • Yoon-Ok Ahn - , Seoul National University College of Medicine (Author)
  • Dong-Hyun Kim - , Hallym University College of Medicine (Author)
  • Isao Oze - , Aichi Cancer Center Hospital and Research Institute (Author)
  • Wanqing Wen - , Vanderbilt University (Author)
  • Keitaro Matsuo - , Aichi Cancer Center Hospital and Research Institute (Author)
  • Koichi Matsuda - , Tokyo University of Science (Author)
  • Chizu Tanikawa - , Tokyo University of Science (Author)
  • Zefang Ren - , Sun Yat-Sen University (Author)
  • Yu-Tang Gao - , Xinhua Hospital affiliated to Shanghai Jiaotong University School of Medicine (Author)
  • Wei-Hua Jia - , Sun Yat-Sen University (Author)
  • John Hopper - , Royal Melbourne Institute of Technology University (Author)
  • Mark Jenkins - , Royal Melbourne Institute of Technology University (Author)
  • Aung Ko Win - , Royal Melbourne Institute of Technology University (Author)
  • Rish Pai - , Department of Laboratory Medicine and Pathology (Author)
  • Jane Figueiredo - , Southern California University of Health Sciences (Author)
  • Robert Haile - , Cedars-Sinai Cancer Research Center for Health Equity (Author)
  • Steven Gallinger - , York University Toronto (Author)
  • Michael Woods - , Memorial University of Newfoundland (Author)
  • Polly Newcomb - , Fred Hutchinson Cancer Research Center (Author)
  • David Duggan - , Translational Genomics Research Institute (Author)
  • Jeremy Cheadle - , Cardiff Metropolitan University (Author)
  • Richard Kaplan - , Medical Research Council (MRC) (Author)
  • Timothy Maughan - , Oxford University Hospitals NHS Foundation Trust (Author)
  • Rachel Kerr - , Oxford University Hospitals NHS Foundation Trust (Author)
  • David Kerr - , Oxford University Hospitals NHS Foundation Trust (Author)
  • Iva Kirac - , University Hospital for Tumors (Author)
  • Jan Böhm - , Department of Pathology (Author)
  • Lukka-Pekka Mecklin - , Central Finland Health Care District (Author)
  • Pekka Jousilahti - , Finnish Institute for Health and Welfare (Author)
  • Paul Knekt - , Finnish Institute for Health and Welfare (Author)
  • Lauri Aaltonen - , Helsinki University Hospital (HUS) (Author)
  • Harri Rissanen - , Finnish Institute for Health and Welfare (Author)
  • Eero Pukkala - , Institute for Statistical and Epidemiological Cancer Research (Author)
  • Johan Eriksson - , Helsinki University Hospital (HUS) (Author)
  • Tatiana Cajuso - , Helsinki University Hospital (HUS) (Author)
  • Ulrika Hänninen - , Helsinki University Hospital (HUS) (Author)
  • Johanna Kondelin - , Helsinki University Hospital (HUS) (Author)
  • Kimmo Palin - , Helsinki University Hospital (HUS) (Author)
  • Tomas Tanskanen - , Helsinki University Hospital (HUS) (Author)
  • Laura Renkonen-Sinisalo - , Helsinki University Hospital (HUS) (Author)
  • Brent Zanke - , York University Toronto (Author)
  • Satu Männistö - , Finnish Institute for Health and Welfare (Author)
  • Demetrius Albanes - , National Cancer Center Institute for Cancer Control (Author)
  • Stephanie Weinstein - , National Cancer Center Institute for Cancer Control (Author)
  • Edward Ruiz-Narvaez - , University of Michigan, Dearborn (UM–Dearborn) (Author)
  • Julie Palmer - , Slone Epidemiology Center at Boston University (Author)
  • Daniel Buchanan - , Royal Melbourne Institute of Technology University (Author)
  • Elizabeth Platz - , Johns Hopkins Bloomberg School of Public Health (Author)
  • Kala Visvanathan - , Johns Hopkins Bloomberg School of Public Health (Author)
  • Cornelia Ulrich - , University of Utah (Author)
  • Erin Siegel - , H. Lee Moffitt Cancer Center & Research Institute (Author)
  • Stefanie Brezina - , Medical University of Vienna (Author)
  • Andrea Gsur - , Medical University of Vienna (Author)
  • Peter Campbell - , Albert Einstein College of Medicine (Author)
  • Jenny Chang-Claude - , German Cancer Research Center (DKFZ) (Author)
  • Michael Hoffmeister - , German Cancer Research Center (DKFZ) (Author)
  • Hermann Brenner - , German Cancer Research Center (DKFZ) (Author)
  • Martha Slattery - , University of Utah (Author)
  • John Potter - , Fred Hutchinson Cancer Research Center (Author)
  • Konstantinos Tsilidis - , University of Ioannina School of Medicine (Author)
  • Matthias Schulze - , German Institute of Human Nutrition Potsdam-Rehbruecke (Author)
  • Marc Gunter - , Nutrition and Metabolism Branch (Author)
  • Neil Murphy - , Nutrition and Metabolism Branch (Author)
  • Antoni Castells - , UIC Barcelona (Author)
  • Sergi Castellví-Bel - , UIC Barcelona (Author)
  • Leticia Moreira - , UIC Barcelona (Author)
  • Volker Arndt - , German Cancer Research Center (DKFZ) (Author)
  • Anna Shcherbina - , Stanford Medicine (Author)
  • Mariana Stern - , Southern California University of Health Sciences (Author)
  • Bens Pardamean - , Bina Nusantara University (Author)
  • Timothy Bishop - , Leeds Trinity University (Author)
  • Graham Giles - , Royal Melbourne Institute of Technology University (Author)
  • Melissa Southey - , Cancer Epidemiology Division (Author)
  • Gregory Idos - , City of Hope National Medical Center (Author)
  • Kevin McDonnell - , Lady Davis Carmel Medical Center and Technion-Israel Institute of Technology (Author)
  • Zomoroda Abu-Ful - , Lady Davis Carmel Medical Center (Author)
  • Joel Greenson - , Lady Davis Carmel Medical Center and Technion-Israel Institute of Technology (Author)
  • Katerina Shulman - , Lady Davis Carmel Medical Center (Author)
  • Flavio Lejbkowicz - , Lady Davis Carmel Medical Center (Author)
  • Kenneth Offit - , Memorial Sloan-Kettering Cancer Center (Author)
  • Yu-Ru Su - , Kaiser Permanente Washington Health Research Institute (Author)
  • Robert Steinfelder - , Fred Hutchinson Cancer Research Center (Author)
  • Temitope Keku - , North Carolina Central University (Author)
  • Bethany van Guelpen - , Umeå University Medical Faculty (Author)
  • Thomas Hudson - , Ontario Institute for Cancer Research (Author)
  • Heather Hampel - , The Ohio State University Comprehensive Cancer Center - The James (Author)
  • Rachel Pearlman - , The Ohio State University Comprehensive Cancer Center - The James (Author)
  • Sonja Berndt - , National Cancer Center Institute for Cancer Control (Author)
  • Richard Hayes - , New York University School of Medicine and New York University Langone Health (Author)
  • Marie Elena Martinez - , University of California at San Diego (Author)
  • Sushma Thomas - , Fred Hutchinson Cancer Research Center (Author)
  • Douglas Corley - , Research and Cooperation Division (Author)
  • Paul Pharoah - , Cambridge University Press (Author)
  • Susanna Larsson - , Karolinska Institutet (Author)
  • Yun Yen - , Taipei Medical University (Author)
  • Heinz-Josef Lenz - , Southern California University of Health Sciences (Author)
  • Emily White - , Fred Hutchinson Cancer Research Center (Author)
  • Li Li - , University Hospitals Cleveland Medical Center (Author)
  • Kimberly Doheny - , Johns Hopkins University School of Medicine (Author)
  • Elizabeth Pugh - , Johns Hopkins University School of Medicine (Author)
  • Tameka Shelford - , Johns Hopkins University School of Medicine (Author)
  • Andrew Chan - , Massachusetts General Hospital (Author)
  • Marcia Cruz-Correa - , University of Puerto Rico (Author)
  • Annika Lindblom - , Karolinska University Hospital (Author)
  • David Hunter - , Harvard University (Author)
  • Amit Joshi - , Massachusetts General Hospital (Author)
  • Clemens Schafmayer - , University Hospital Rostock (Author)
  • Peter Scacheri - , University Hospitals Cleveland Medical Center (Author)
  • Anshul Kundaje - , Stanford Medicine (Author)
  • Deborah Nickerson - , George Washington University (GWU) (Author)
  • Robert Schoen - , University of Pittsburgh Medical Center (UPMC) (Author)
  • Jochen Hampe - , Department of internal Medicine I (Author)
  • Zsofia Stadler - , Weill Cornell Medical College in Qatar (Author)
  • Pavel Vodicka - , Institute of Experimental Medicine of the Czech Academy of Sciences (Author)
  • Ludmila Vodickova - , Institute of Experimental Medicine of the Czech Academy of Sciences (Author)
  • Veronika Vymetalkova - , Institute of Experimental Medicine of the Czech Academy of Sciences (Author)
  • Nickolas Papadopoulos - , Johns Hopkins University School of Medicine (Author)
  • Chistopher Edlund - , Southern California University of Health Sciences (Author)
  • William Gauderman - , Southern California University of Health Sciences (Author)
  • Duncan Thomas - , Southern California University of Health Sciences (Author)
  • David Shibata - , University of Tennessee Health Science Center (Author)
  • Amanda Toland - , The Ohio State University College of Medicine (Author)
  • Sanford Markowitz - , University Hospitals Cleveland Medical Center (Author)
  • Andre Kim - , Southern California University of Health Sciences (Author)
  • Stephen Chanock - , National Cancer Center Institute for Cancer Control (Author)
  • Franzel van Duijnhoven - , Wageningen University & Research (WUR) (Author)
  • Edith Feskens - , Wageningen University & Research (WUR) (Author)
  • Lori Sakoda - , Fred Hutchinson Cancer Research Center (Author)
  • Manuela Gago-Dominguez - , Genomic Medicine Group (Author)
  • Alicja Wolk - , Karolinska Institutet (Author)
  • Alessio Naccarati - , Candiolo Cancer Institute FPO-IRCCS (Author)
  • Barbara Pardini - , Candiolo Cancer Institute FPO-IRCCS (Author)
  • Liesel FitzGerald - , Cancer Epidemiology Division (Author)
  • Soo Chin Lee - , Duke-NUS Medical School (Author)
  • Shuji Ogino - , Harvard University (Author)
  • Stephanie Bien - , Fred Hutchinson Cancer Research Center (Author)
  • Charles Kooperberg - , Fred Hutchinson Cancer Research Center (Author)
  • Christopher Li - , Fred Hutchinson Cancer Research Center (Author)
  • Yi Lin - , Fred Hutchinson Cancer Research Center (Author)
  • Ross Prentice - , Fred Hutchinson Cancer Research Center (Author)
  • Chenxu Qu - , Fred Hutchinson Cancer Research Center (Author)
  • Stéphane Bézieau - , Centre Hospitalier Universitaire Nantes (Author)
  • Catherine Tangen - , SWOG Statistical Center (Author)
  • Elaine Mardis - , The Steve and Cindy Rasmussen Institute for Genomic Medicine (Author)
  • Taiki Yamaji - , National Cancer Center Institute for Cancer Control (Author)
  • Norie Sawada - , National Cancer Center Institute for Cancer Control (Author)
  • Motoki Iwasaki - , National Cancer Center Institute for Cancer Control (Author)
  • Christopher Haiman - , Southern California University of Health Sciences (Author)
  • Loic Le Marchand - , Brigham Young University Hawaii (Author)
  • Anna Wu - , Southern California University of Health Sciences (Author)
  • Chenxu Qu - , Southern California University of Health Sciences (Author)
  • Caroline McNeil - , Southern California University of Health Sciences (Author)
  • Gerhard Coetzee - , Van Andel Institute (Author)
  • Caroline Hayward - , Edinburgh Napier University (Author)
  • Ian Deary - , Edinburgh Napier University (Author)
  • Sarah Harris - , Edinburgh Napier University (Author)
  • Evropi Theodoratou - , Edinburgh Napier University (Author)
  • Stuart Reid - , Edinburgh Napier University (Author)
  • Marion Walker - , Edinburgh Napier University (Author)
  • Li Yin Ooi - , Edinburgh Napier University (Author)
  • Victor Moreno - , Bellvitge Biomedical Research Institute (IDIBELL) (Author)
  • Graham Casey - , West Virginia University (Author)
  • Stephen Gruber - , City of Hope National Medical Center (Author)
  • Ian Tomlinson - , Edinburgh Napier University (Author)
  • Wei Zheng - , Vanderbilt University (Author)
  • Malcolm Dunlop - , Edinburgh Napier University (Author)
  • Richard Houlston - , Children's Cancer Institute Australia Lowy Cancer Research Centre (Author)
  • Ulrike Peters - , Fred Hutchinson Cancer Research Center (Author)

Abstract

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.

Details

Original languageEnglish
Pages (from-to)89-99
Number of pages11
JournalNature genetics
Volume55
Issue number1
Publication statusPublished - Jan 2023
Peer-reviewedYes

External IDs

PubMedCentral PMC10094749
Scopus 85144441436

Keywords

Sustainable Development Goals

Keywords

  • Humans, Colorectal Neoplasms/genetics, East Asian People/genetics, European People/genetics, Genetic Predisposition to Disease, Genome-Wide Association Study, Multiomics, Polymorphism, Single Nucleotide/genetics