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

Zhishan Chen, Xingyi Guo, Ran Tao, Jeroen R. Huyghe, Philip J. Law, Ceres Fernandez-Rozadilla, Jie Ping, Guochong Jia, Jirong Long, Chao Li, Quanhu Shen, Yuhan Xie, Maria N. Timofeeva, Minta Thomas, Stephanie L. Schmit, Virginia Díez-Obrero, Matthew Devall, Ferran Moratalla-Navarro, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah E. W. Briggs, Victoria Svinti, Kevin Donnelly, Susan M. Farrington, James Blackmur, Peter G. Vaughan-Shaw, Xiao-Ou Shu, Yingchang Lu, Peter Broderick, James Studd, Tabitha A. Harrison, David V. Conti, Fredrick R. Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Jae Hwan Oh, Jeongseon Kim, Sun Ha Jee, Keum Ji Jung, Sun-Seog Kweon, Min-Ho Shin, Aesun Shin, Yoon-Ok Ahn, Dong-Hyun Kim, Isao Oze, Wanqing Wen, Keitaro Matsuo, Koichi Matsuda, Chizu Tanikawa, Zefang Ren, Yu-Tang Gao, Wei-Hua Jia, John L. Hopper, Mark A. Jenkins, Aung Ko Win, Rish K. Pai, Jane C. Figueiredo, Robert W. Haile, Steven Gallinger, Michael O. Woods, Polly A. Newcomb, David Duggan, Jeremy P. Cheadle, Richard Kaplan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Jukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri A. Aaltonen, Harri Rissanen, Eero Pukkala, Johan G. Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Satu Männistö, Demetrius Albanes, Stephanie J. Weinstein, Edward Ruiz-Narvaez, Julie R. Palmer, Daniel D. Buchanan, Elizabeth A. Platz, Kala Visvanathan, Cornelia M. Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter T. Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha L. Slattery, John D. Potter, Kostas K. Tsilidis, Matthias B. Schulze, Marc J. Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, D. Timothy Bishop, Graham G. Giles, Melissa C. Southey, Gregory E. Idos, Kevin J. McDonnell, Zomoroda Abu-Ful, Joel K. Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope O. Keku, Bethany Guelpen, Thomas J. Hudson, Heather Hampel, Rachel Pearlman, Sonja I. Berndt, Richard B. Hayes, Marie Elena Martinez, Sushma S. Thomas, Paul D. P. Pharoah, Susanna C. Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly F. Doheny, Elizabeth Pugh, Tameka Shelford, Andrew T. Chan, Marcia Cruz-Correa, Annika Lindblom, David J. Hunter, Amit D. Joshi, Clemens Schafmayer, Peter C. Scacheri, Anshul Kundaje, Robert E. Schoen, Jochen Hampe, Zsofia K. Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Christopher K. Edlund, W. James Gauderman, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen J. Chanock, Franzel Duijnhoven, Edith J. M. Feskens, Lori C. Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Barbara Pardini, Liesel M. FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie A. Bien, Charles Kooperberg, Christopher I. Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Loic Marchand, Anna H. Wu, Chenxu Qu, Caroline E. McNeil, Gerhard Coetzee, Caroline Hayward, Ian J. Deary, Sarah E. Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Ken S. Lau, Hongyu Zhao, Li Hsu, Qiuyin Cai, Malcolm G. Dunlop, Stephen B. Gruber, Richard S. Houlston, Victor Moreno, Graham Casey, Ulrike Peters, Ian Tomlinson and Wei Zheng ()
Additional contact information
Zhishan Chen: Vanderbilt University Medical Center
Xingyi Guo: Vanderbilt University Medical Center
Ran Tao: Vanderbilt University Medical Center
Jeroen R. Huyghe: Fred Hutchinson Cancer Center
Philip J. Law: Institute of Cancer Research
Ceres Fernandez-Rozadilla: University of Edinburgh
Jie Ping: Vanderbilt University Medical Center
Guochong Jia: Vanderbilt University Medical Center
Jirong Long: Vanderbilt University Medical Center
Chao Li: Vanderbilt University Medical Center
Quanhu Shen: Vanderbilt University Medical Center
Yuhan Xie: Yale School of Public Health
Maria N. Timofeeva: University of Edinburgh
Minta Thomas: Fred Hutchinson Cancer Center
Stephanie L. Schmit: Cleveland Clinic
Virginia Díez-Obrero: Bellvitge Biomedical Research Institute
Matthew Devall: University of Virginia
Ferran Moratalla-Navarro: Bellvitge Biomedical Research Institute
Juan Fernandez-Tajes: University of Edinburgh
Claire Palles: University of Birmingham
Kitty Sherwood: University of Edinburgh
Sarah E. W. Briggs: University of Oxford
Victoria Svinti: University of Edinburgh
Kevin Donnelly: University of Edinburgh
Susan M. Farrington: University of Edinburgh
James Blackmur: University of Edinburgh
Peter G. Vaughan-Shaw: University of Edinburgh
Xiao-Ou Shu: Vanderbilt University Medical Center
Yingchang Lu: Vanderbilt University Medical Center
Peter Broderick: Institute of Cancer Research
James Studd: Institute of Cancer Research
Tabitha A. Harrison: Fred Hutchinson Cancer Center
David V. Conti: University of Southern California
Fredrick R. Schumacher: Case Western Reserve University
Marilena Melas: Nationwide Children’s Hospital
Gad Rennert: Clalit National Cancer Control Center
Mireia Obón-Santacana: Bellvitge Biomedical Research Institute
Vicente Martín-Sánchez: Consortium for Biomedical Research in Epidemiology and Public Health
Jae Hwan Oh: National Cancer Center
Jeongseon Kim: National Cancer Center
Sun Ha Jee: Yonsei University
Keum Ji Jung: Yonsei University
Sun-Seog Kweon: Chonnam National University Medical School
Min-Ho Shin: Chonnam National University Medical School
Aesun Shin: Seoul National University
Yoon-Ok Ahn: Seoul National University College of Medicine
Dong-Hyun Kim: Hallym University College of Medicine
Isao Oze: Aichi Cancer Center Research Institute
Wanqing Wen: Vanderbilt University Medical Center
Keitaro Matsuo: Nagoya University Graduate School of Medicine
Koichi Matsuda: University of Tokyo
Chizu Tanikawa: University of Tokyo
Zefang Ren: Sun Yat-sen University
Yu-Tang Gao: Shanghai Jiaotong University School of Medicine
Wei-Hua Jia: Sun Yat-sen University
John L. Hopper: University of Melbourne
Mark A. Jenkins: University of Melbourne
Aung Ko Win: University of Melbourne
Rish K. Pai: Mayo Clinic Arizona
Jane C. Figueiredo: University of Southern California
Robert W. Haile: Cedars-Sinai Cancer Research Center for Health Equity
Steven Gallinger: University of Toronto
Michael O. Woods: Memorial University of Newfoundland
Polly A. Newcomb: Fred Hutchinson Cancer Center
David Duggan: Translational Genomics Research Institute
Jeremy P. Cheadle: Cardiff University
Richard Kaplan: Medical Research Council
Rachel Kerr: University of Oxford
David Kerr: University of Oxford
Iva Kirac: Sestre milosrdnice University Hospital Center
Jan Böhm: Central Finland Health Care District
Jukka-Pekka Mecklin: Central Finland Health Care District
Pekka Jousilahti: Finnish Institute for Health and Welfare
Paul Knekt: Finnish Institute for Health and Welfare
Lauri A. Aaltonen: University of Helsinki
Harri Rissanen: Finnish Institute for Health and Welfare
Eero Pukkala: Tampere University
Johan G. Eriksson: University of Helsinki
Tatiana Cajuso: University of Helsinki
Ulrika Hänninen: University of Helsinki
Johanna Kondelin: University of Helsinki
Kimmo Palin: University of Helsinki
Tomas Tanskanen: University of Helsinki
Laura Renkonen-Sinisalo: Helsinki University Hospital
Satu Männistö: Finnish Institute for Health and Welfare
Demetrius Albanes: National Institutes of Health
Stephanie J. Weinstein: National Institutes of Health
Edward Ruiz-Narvaez: University of Michigan
Julie R. Palmer: Boston University School of Medicine
Daniel D. Buchanan: University of Melbourne
Elizabeth A. Platz: Johns Hopkins Bloomberg School of Public Health
Kala Visvanathan: Johns Hopkins Bloomberg School of Public Health
Cornelia M. Ulrich: University of Utah
Erin Siegel: H. Lee Moffitt Cancer Center and Research Institute
Stefanie Brezina: Medical University Vienna
Andrea Gsur: Medical University Vienna
Peter T. Campbell: Albert Einstein College of Medicine
Jenny Chang-Claude: German Cancer Research Center
Michael Hoffmeister: German Cancer Research Center
Hermann Brenner: German Cancer Research Center
Martha L. Slattery: University of Utah
John D. Potter: Fred Hutchinson Cancer Center
Kostas K. Tsilidis: Imperial College London
Matthias B. Schulze: German Institute of Human Nutrition Potsdam-Rehbruecke
Marc J. Gunter: World Health Organization
Neil Murphy: World Health Organization
Antoni Castells: University of Barcelona
Sergi Castellví-Bel: University of Barcelona
Leticia Moreira: University of Barcelona
Volker Arndt: German Cancer Research Center
Anna Shcherbina: Stanford University
D. Timothy Bishop: University of Leeds
Graham G. Giles: University of Melbourne
Melissa C. Southey: Cancer Council Victoria
Gregory E. Idos: City of Hope National Medical Center
Kevin J. McDonnell: Clalit National Cancer Control Center
Zomoroda Abu-Ful: Lady Davis Carmel Medical Center
Joel K. Greenson: Clalit National Cancer Control Center
Katerina Shulman: Lady Davis Carmel Medical Center
Flavio Lejbkowicz: Clalit National Cancer Control Center
Kenneth Offit: Memorial Sloan-Kettering Cancer Center
Yu-Ru Su: Kaiser Permanente Washington Health Research Institute
Robert Steinfelder: Fred Hutchinson Cancer Center
Temitope O. Keku: University of North Carolina
Bethany Guelpen: Umeå University
Thomas J. Hudson: Ontario Institute for Cancer Research
Heather Hampel: Ohio State University Comprehensive Cancer Center
Rachel Pearlman: Ohio State University Comprehensive Cancer Center
Sonja I. Berndt: National Institutes of Health
Richard B. Hayes: New York University School of Medicine
Marie Elena Martinez: University of California San Diego
Sushma S. Thomas: Fred Hutchinson Cancer Center
Paul D. P. Pharoah: University of Cambridge
Susanna C. Larsson: Karolinska Institutet
Yun Yen: Taipei Medical University
Heinz-Josef Lenz: University of Southern California
Emily White: Fred Hutchinson Cancer Center
Li Li: Case Western Reserve University
Kimberly F. Doheny: Johns Hopkins University School of Medicine
Elizabeth Pugh: Johns Hopkins University School of Medicine
Tameka Shelford: Johns Hopkins University School of Medicine
Andrew T. Chan: Broad Institute of Harvard and MIT
Marcia Cruz-Correa: University of Puerto Rico
Annika Lindblom: Karolinska University Hospital
David J. Hunter: Harvard University
Amit D. Joshi: Massachusetts General Hospital and Harvard Medical School
Clemens Schafmayer: University Hospital Rostock
Peter C. Scacheri: Case Western Reserve University
Anshul Kundaje: Stanford University
Robert E. Schoen: University of Pittsburgh Medical Center
Jochen Hampe: Technische Universität Dresden
Zsofia K. Stadler: Weill Cornell Medical College
Pavel Vodicka: Institute of Experimental Medicine of the Czech Academy of Sciences
Ludmila Vodickova: Institute of Experimental Medicine of the Czech Academy of Sciences
Veronika Vymetalkova: Institute of Experimental Medicine of the Czech Academy of Sciences
Christopher K. Edlund: University of Southern California
W. James Gauderman: University of Southern California
David Shibata: University of Tennessee Health Science Center
Amanda Toland: Ohio State University
Sanford Markowitz: Case Western Reserve University and University Hospitals of Cleveland
Andre Kim: University of Southern California
Stephen J. Chanock: National Institutes of Health
Franzel Duijnhoven: Wageningen University and Research
Edith J. M. Feskens: Wageningen University and Research
Lori C. Sakoda: Fred Hutchinson Cancer Center
Manuela Gago-Dominguez: Servicio Galego de Saude
Alicja Wolk: Karolinska Institutet
Barbara Pardini: Candiolo Cancer Institute FPO-IRCCS
Liesel M. FitzGerald: Cancer Council Victoria
Soo Chin Lee: National University of Singapore
Shuji Ogino: Harvard University
Stephanie A. Bien: Fred Hutchinson Cancer Center
Charles Kooperberg: Fred Hutchinson Cancer Center
Christopher I. Li: Fred Hutchinson Cancer Center
Yi Lin: Fred Hutchinson Cancer Center
Ross Prentice: Fred Hutchinson Cancer Center
Conghui Qu: Fred Hutchinson Cancer Center
Stéphane Bézieau: Centre Hospitalier Universitaire Nantes
Taiki Yamaji: National Cancer Center
Norie Sawada: National Cancer Center
Motoki Iwasaki: National Cancer Center
Loic Marchand: University of Hawaii
Anna H. Wu: University of Southern California
Chenxu Qu: University of Southern California
Caroline E. McNeil: University of Southern California
Gerhard Coetzee: Van Andel Research Institute
Caroline Hayward: University of Edinburgh
Ian J. Deary: University of Edinburgh
Sarah E. Harris: University of Edinburgh
Evropi Theodoratou: University of Edinburgh
Stuart Reid: University of Edinburgh
Marion Walker: University of Edinburgh
Li Yin Ooi: University of Edinburgh
Ken S. Lau: Vanderbilt University School of Medicine
Hongyu Zhao: Yale School of Public Health
Li Hsu: Fred Hutchinson Cancer Center
Qiuyin Cai: Vanderbilt University Medical Center
Malcolm G. Dunlop: University of Edinburgh
Stephen B. Gruber: City of Hope National Medical Center
Richard S. Houlston: Institute of Cancer Research
Victor Moreno: Bellvitge Biomedical Research Institute
Graham Casey: University of Virginia
Ulrike Peters: Fred Hutchinson Cancer Center
Ian Tomlinson: University of Edinburgh
Wei Zheng: Vanderbilt University Medical Center

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47399-x

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