Discovery of common and rare genetic risk variants for colorectal cancer

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • Jeroen R. Huyghe - , Fred Hutchinson Cancer Research Center (Author)
  • Stephanie A. Bien - , Fred Hutchinson Cancer Research Center (Author)
  • Tabitha A. Harrison - , Fred Hutchinson Cancer Research Center (Author)
  • Hyun Min Kang - , University of Michigan, Ann Arbor (Author)
  • Sai Chen - , University of Michigan, Ann Arbor (Author)
  • Stephanie L. Schmit - , University of South Florida (Author)
  • David V. Conti - , University of Southern California (Author)
  • Conghui Qu - , Fred Hutchinson Cancer Research Center (Author)
  • Jihyoun Jeon - , University of Michigan, Ann Arbor (Author)
  • Christopher K. Edlund - , University of Southern California (Author)
  • Peyton Greenside - , Stanford University (Author)
  • Michael Wainberg - , Stanford University (Author)
  • Fredrick R. Schumacher - , Case Western Reserve University (Author)
  • Joshua D. Smith - , University of Washington (Author)
  • David M. Levine - , University of Washington (Author)
  • Sarah C. Nelson - , University of Washington (Author)
  • Nasa A. Sinnott-Armstrong - , Stanford University (Author)
  • Demetrius Albanes - , National Cancer Institute (NCI) (Author)
  • M. Henar Alonso - , Institute Catala Oncologia, CIBER - Center for Biomedical Research Network, University of Barcelona (Author)
  • Kristin Anderson - , University of Minnesota System (Author)
  • Coral Arnau-Collell - , University of Barcelona (Author)
  • Volker Arndt - , German Cancer Research Center (DKFZ) (Author)
  • Christina Bamia - , Helenic Health Foundation, National and Kapodistrian University of Athens (Author)
  • Barbara L. Banbury - , Fred Hutchinson Cancer Research Center (Author)
  • John A. Baron - , University of North Carolina at Chapel Hill (Author)
  • Sonja I. Berndt - , National Cancer Institute (NCI) (Author)
  • Stéphane Bézieau - , Université de Nantes (Author)
  • D. Timothy Bishop - , University of Leeds (Author)
  • Juergen Boehm - , University of Utah (Author)
  • Heiner Boeing - , German Institute of Human Nutrition Potsdam-Rehbruecke (Author)
  • Hermann Brenner - , German Cancer Research Center (DKFZ) (Author)
  • Stefanie Brezina - , Medical University of Vienna (Author)
  • Stephan Buch - , Department of internal Medicine I (Author)
  • Daniel D. Buchanan - , University of Melbourne, Royal Melbourne Hospital (Author)
  • Andrea Burnett-Hartman - , Kaiser Permanente (Author)
  • Katja Butterbach - , German Cancer Research Center (DKFZ) (Author)
  • Bette J. Caan - , Kaiser Permanente (Author)
  • Peter T. Campbell - , American Cancer Society (Author)
  • Christopher S. Carlson - , Fred Hutchinson Cancer Research Center, University of Washington (Author)
  • Sergi Castellví-Bel - , University of Barcelona (Author)
  • Andrew T. Chan - , Harvard University, Broad Institute of Harvard University and MIT (Author)
  • Jenny Chang-Claude - , German Cancer Research Center (DKFZ), University of Hamburg (Author)
  • Stephen J. Chanock - , National Cancer Institute (NCI) (Author)
  • Maria Dolores Chirlaque - , CIBER - Center for Biomedical Research Network, University of Murcia (Author)
  • Sang Hee Cho - , Chonnam National University (Author)
  • Charles M. Connolly - , Fred Hutchinson Cancer Research Center (Author)
  • Amanda J. Cross - , Imperial College London (Author)
  • Katarina Cuk - , German Cancer Research Center (DKFZ) (Author)
  • Keith R. Curtis - , Fred Hutchinson Cancer Research Center (Author)
  • Albert de la Chapelle - , Ohio State University (Author)
  • Kimberly F. Doheny - , Johns Hopkins University (Author)
  • David Duggan - , Translational Genomics Research Institute (Author)
  • Douglas F. Easton - , University of Cambridge (Author)
  • Sjoerd G. Elias - , Utrecht University (Author)
  • Faye Elliott - , University of Leeds (Author)
  • Dallas R. English - , University of Melbourne, Cancer Council Victoria (Author)
  • Edith J.M. Feskens - , Wageningen University & Research (WUR) (Author)
  • Jane C. Figueiredo - , Cedars-Sinai Medical Center, University of Southern California (Author)
  • Rocky Fischer - , University of Michigan, Ann Arbor (Author)
  • Liesel M. FitzGerald - , Cancer Council Victoria, University of Tasmania (Author)
  • David Forman - , International Agency for Research on Cancer (Author)
  • Manish Gala - , Harvard University (Author)
  • Steven Gallinger - , University of Toronto (Author)
  • W. James Gauderman - , University of Southern California (Author)
  • Graham G. Giles - , University of Melbourne, Cancer Council Victoria (Author)
  • Elizabeth Gillanders - , National Cancer Institute (NCI) (Author)
  • Jian Gong - , Fred Hutchinson Cancer Research Center (Author)
  • Phyllis J. Goodman - , Fred Hutchinson Cancer Research Center (Author)
  • William M. Grady - , Fred Hutchinson Cancer Research Center (Author)
  • John S. Grove - , University of Hawai'i at Mānoa (Author)
  • Andrea Gsur - , Medical University of Vienna (Author)
  • Marc J. Gunter - , International Agency for Research on Cancer (Author)
  • Robert W. Haile - , Stanford University (Author)
  • Jochen Hampe - , Department of internal Medicine I (Author)
  • Heather Hampel - , Ohio State University (Author)
  • Sophia Harlid - , Umeå University (Author)
  • Richard B. Hayes - , New York University (Author)
  • Philipp Hofer - , Medical University of Vienna (Author)
  • Michael Hoffmeister - , German Cancer Research Center (DKFZ) (Author)
  • John L. Hopper - , University of Melbourne, Seoul National University (Author)
  • Li Hsu - , University of Washington (Author)
  • Wen Yi Huang - , National Cancer Institute (NCI) (Author)
  • Thomas J. Hudson - , Ontario Institute for Cancer Research (Author)
  • David J. Hunter - , Harvard University, University of Oxford (Author)
  • Gemma Ibañez-Sanz - , Institute Catala Oncologia, University of Barcelona (Author)
  • Gregory E. Idos - , University of Southern California (Author)
  • Roxann Ingersoll - , Johns Hopkins University (Author)
  • Rebecca D. Jackson - , Ohio State University (Author)
  • Eric J. Jacobs - , American Cancer Society (Author)
  • Mark A. Jenkins - , University of Melbourne (Author)
  • Amit D. Joshi - , Harvard University (Author)
  • Corinne E. Joshu - , Johns Hopkins University (Author)
  • Temitope O. Keku - , University of North Carolina at Chapel Hill (Author)
  • Timothy J. Key - , University of Oxford (Author)
  • Hyeong Rok Kim - , Chonnam National University (Author)
  • Emiko Kobayashi - , Fred Hutchinson Cancer Research Center (Author)
  • Laurence N. Kolonel - , University of Hawai'i at Mānoa (Author)
  • Charles Kooperberg - , Fred Hutchinson Cancer Research Center (Author)
  • Tilman Kühn - , German Cancer Research Center (DKFZ) (Author)
  • Sébastien Küry - , Université de Nantes (Author)
  • Sun Seog Kweon - , Chonnam National University (Author)
  • Susanna C. Larsson - , Karolinska Institutet (Author)
  • Cecelia A. Laurie - , University of Washington (Author)
  • Loic Le Marchand - , University of Hawai'i at Mānoa (Author)
  • Suzanne M. Leal - , Baylor College of Medicine (Author)
  • Soo Chin Lee - , National University Cancer Institute, National University of Singapore (Author)
  • Flavio Lejbkowicz - , Clalit Health Services, Carmel Medical Center (Author)
  • Mathieu Lemire - , Ontario Institute for Cancer Research (Author)
  • Christopher I. Li - , Fred Hutchinson Cancer Research Center (Author)
  • Li Li - , Case Western Reserve University (Author)
  • Wolfgang Lieb - , Kiel University (Author)
  • Yi Lin - , Fred Hutchinson Cancer Research Center (Author)
  • Annika Lindblom - , Karolinska Institutet (Author)
  • Noralane M. Lindor - , Mayo Clinic Scottsdale, AZ (Author)
  • Hua Ling - , Johns Hopkins University (Author)
  • Tin L. Louie - , University of Washington (Author)
  • Satu Männistö - , National Institute for Health and Welfare (Author)
  • Sanford D. Markowitz - , Case Western Reserve University (Author)
  • Vicente Martín - , CIBER - Center for Biomedical Research Network, University of Leon (Author)
  • Giovanna Masala - , Institute for the Study and Prevention of Cancer (Author)
  • Caroline E. McNeil - , University of Southern California (Author)
  • Marilena Melas - , University of Southern California (Author)
  • Roger L. Milne - , University of Melbourne, Cancer Council Victoria (Author)
  • Lorena Moreno - , University of Barcelona (Author)
  • Neil Murphy - , International Agency for Research on Cancer (Author)
  • Robin Myte - , Umeå University (Author)
  • Alessio Naccarati - , Czech Academy of Sciences, Italian Institute for Genomic Medicine (IIGM) (Author)
  • Polly A. Newcomb - , Fred Hutchinson Cancer Research Center, University of Washington (Author)
  • Kenneth Offit - , Memorial Sloan-Kettering Cancer Center, Cornell University (Author)
  • Shuji Ogino - , Broad Institute of Harvard University and MIT, Harvard University, Dana-Farber Cancer Institute (Author)
  • N. Charlotte Onland-Moret - , Utrecht University (Author)
  • Barbara Pardini - , Italian Institute for Genomic Medicine (IIGM), University of Turin (Author)
  • Patrick S. Parfrey - , Memorial University of Newfoundland (Author)
  • Rachel Pearlman - , Ohio State University (Author)
  • Vittorio Perduca - , Universite Paris Descartes, Université de Versailles Saint-Quentin-en-Yvelines (Author)
  • Paul D.P. Pharoah - , University of Cambridge (Author)
  • Mila Pinchev - , Carmel Medical Center (Author)
  • Elizabeth A. Platz - , Johns Hopkins University (Author)
  • Ross L. Prentice - , Fred Hutchinson Cancer Research Center (Author)
  • Elizabeth Pugh - , Johns Hopkins University (Author)
  • Leon Raskin - , Vanderbilt University (Author)
  • Gad Rennert - , Carmel Medical Center, Clalit Health Services, Technion-Israel Institute of Technology (Author)
  • Hedy S. Rennert - , Carmel Medical Center, Clalit Health Services, Technion-Israel Institute of Technology (Author)
  • Elio Riboli - , Imperial College London (Author)
  • Miguel Rodríguez-Barranco - , CIBER - Center for Biomedical Research Network, Escuela Andaluza de Salud Publica (Author)
  • Jane Romm - , Johns Hopkins University (Author)
  • Lori C. Sakoda - , Fred Hutchinson Cancer Research Center, Kaiser Permanente (Author)
  • Clemens Schafmayer - , Kiel University (Author)
  • Robert E. Schoen - , University of Pittsburgh (Author)
  • Daniela Seminara - , National Cancer Institute (NCI) (Author)
  • Mitul Shah - , University of Cambridge (Author)
  • Tameka Shelford - , Johns Hopkins University (Author)
  • Min Ho Shin - , Chonnam National University (Author)
  • Katerina Shulman - , Hille Yaffe Medical Center Israel (Author)
  • Sabina Sieri - , IRCCS Fondazione Istituto Nazionale per lo studio e la cura dei tumori - Milano (Author)
  • Martha L. Slattery - , University of Utah (Author)
  • Melissa C. Southey - , University of Melbourne (Author)
  • Zsofia K. Stadler - , Memorial Sloan-Kettering Cancer Center (Author)
  • Christa Stegmaier - , Saarland Cancer Registry (Author)
  • Yu Ru Su - , Fred Hutchinson Cancer Research Center (Author)
  • Catherine M. Tangen - , Fred Hutchinson Cancer Research Center (Author)
  • Stephen N. Thibodeau - , Mayo Clinic Rochester, MN (Author)
  • Duncan C. Thomas - , University of Southern California (Author)
  • Sushma S. Thomas - , Fred Hutchinson Cancer Research Center (Author)
  • Amanda E. Toland - , Ohio State University (Author)
  • Antonia Trichopoulou - , Helenic Health Foundation, National and Kapodistrian University of Athens (Author)
  • Cornelia M. Ulrich - , University of Utah (Author)
  • David J. Van Den Berg - , University of Southern California (Author)
  • Franzel J.B. van Duijnhoven - , Wageningen University & Research (WUR) (Author)
  • Bethany Van Guelpen - , Umeå University (Author)
  • Henk van Kranen - , National Institute of Public Health and the Environment (Author)
  • Joseph Vijai - , Memorial Sloan-Kettering Cancer Center (Author)
  • Kala Visvanathan - , Johns Hopkins University (Author)
  • Pavel Vodicka - , Czech Academy of Sciences, Charles University Prague (Author)
  • Ludmila Vodickova - , Czech Academy of Sciences, Charles University Prague (Author)
  • Veronika Vymetalkova - , Czech Academy of Sciences, Charles University Prague (Author)
  • Korbinian Weigl - , German Cancer Research Center (DKFZ), Heidelberg University  (Author)
  • Stephanie J. Weinstein - , National Cancer Institute (NCI) (Author)
  • Emily White - , Fred Hutchinson Cancer Research Center (Author)
  • Aung Ko Win - , Royal Melbourne Hospital, University of Melbourne (Author)
  • C. Roland Wolf - , University of Dundee (Author)
  • Alicja Wolk - , Karolinska Institutet, Uppsala University (Author)
  • Michael O. Woods - , Memorial University of Newfoundland (Author)
  • Anna H. Wu - , University of Southern California (Author)
  • Syed H. Zaidi - , Ontario Institute for Cancer Research (Author)
  • Brent W. Zanke - , University of Toronto (Author)
  • Qing Zhang - , Fred Hutchinson Cancer Research Center (Author)
  • Wei Zheng - , Vanderbilt University (Author)
  • Peter C. Scacheri - , Case Western Reserve University (Author)
  • John D. Potter - , Fred Hutchinson Cancer Research Center (Author)
  • Michael C. Bassik - , Stanford University (Author)
  • Anshul Kundaje - , Stanford University (Author)
  • Graham Casey - , University of Virginia (Author)
  • Victor Moreno - , Institute Catala Oncologia, CIBER - Center for Biomedical Research Network, University of Barcelona (Author)
  • Goncalo R. Abecasis - , University of Michigan, Ann Arbor (Author)
  • Deborah A. Nickerson - , University of Washington (Author)
  • Stephen B. Gruber - , University of Southern California (Author)
  • Li Hsu - , Fred Hutchinson Cancer Research Center, University of Washington (Author)
  • Ulrike Peters - , Fred Hutchinson Cancer Research Center, University of Washington (Author)

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.

Details

Original languageEnglish
Pages (from-to)76-87
Number of pages12
JournalNature genetics
Volume51
Issue number1
Publication statusPublished - 1 Jan 2019
Peer-reviewedYes

External IDs

PubMed 30510241
ORCID /0000-0003-2928-015X/work/146166305

Keywords

Sustainable Development Goals

ASJC Scopus subject areas