Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
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. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
Authors:
Ceres Fernandez-Rozadilla, Maria Timofeeva, Zhishan Chen, Philip Law, Minta Thomas, Stephanie Schmit, Virginia Díez-Obrero, Li Hsu, Juan Fernandez-Tajes, Claire Palles, Kitty Sherwood, Sarah Briggs, Victoria Svinti, Kevin Donnelly, Susan Farrington, James Blackmur, Peter Vaughan-Shaw, Xiao-ou Shu, Jirong Long, Qiuyin Cai, Xingyi Guo, Yingchang Lu, Peter Broderick, James Studd, Jeroen Huyghe, Tabitha Harrison, David Conti, Christopher Dampier, Mathew Devall, Fredrick Schumacher, Marilena Melas, Gad Rennert, Mireia Obón-Santacana, Vicente Martín-Sánchez, Ferran Moratalla-Navarro, 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 Hopper, Mark Jenkins, Aung Ko Win, Rish Pai, Jane Figueiredo, Robert Haile, Steven Gallinger, Michael Woods, Polly Newcomb, David Duggan, Jeremy Cheadle, Richard Kaplan, Timothy Maughan, Rachel Kerr, David Kerr, Iva Kirac, Jan Böhm, Lukka-Pekka Mecklin, Pekka Jousilahti, Paul Knekt, Lauri Aaltonen, Harri Rissanen, Eero Pukkala, Johan Eriksson, Tatiana Cajuso, Ulrika Hänninen, Johanna Kondelin, Kimmo Palin, Tomas Tanskanen, Laura Renkonen-Sinisalo, Brent Zanke, Satu Männistö, Demetrius Albanes, Stephanie Weinstein, Edward Ruiz-Narvaez, Julie Palmer, Daniel Buchanan, Elizabeth Platz, Kala Visvanathan, Cornelia Ulrich, Erin Siegel, Stefanie Brezina, Andrea Gsur, Peter Campbell, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Martha Slattery, John Potter, Konstantinos Tsilidis, Matthias Schulze, Marc Gunter, Neil Murphy, Antoni Castells, Sergi Castellví-Bel, Leticia Moreira, Volker Arndt, Anna Shcherbina, Mariana Stern, Bens Pardamean, Timothy Bishop, Graham Giles, Melissa Southey, Gregory Idos, Kevin McDonnell, Zomoroda Abu-Ful, Joel Greenson, Katerina Shulman, Flavio Lejbkowicz, Kenneth Offit, Yu-Ru Su, Robert Steinfelder, Temitope Keku, Bethany van Guelpen, Thomas Hudson, Heather Hampel, Rachel Pearlman, Sonja Berndt, Richard Hayes, Marie Elena Martinez, Sushma Thomas, Douglas Corley, Paul Pharoah, Susanna Larsson, Yun Yen, Heinz-Josef Lenz, Emily White, Li Li, Kimberly Doheny, Elizabeth Pugh, Tameka Shelford, Andrew Chan, Marcia Cruz-Correa, Annika Lindblom, David Hunter, Amit Joshi, Clemens Schafmayer, Peter Scacheri, Anshul Kundaje, Deborah Nickerson, Robert Schoen, Jochen Hampe, Zsofia Stadler, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Nickolas Papadopoulos, Chistopher Edlund, William Gauderman, Duncan Thomas, David Shibata, Amanda Toland, Sanford Markowitz, Andre Kim, Stephen Chanock, Franzel van Duijnhoven, Edith Feskens, Lori Sakoda, Manuela Gago-Dominguez, Alicja Wolk, Alessio Naccarati, Barbara Pardini, Liesel FitzGerald, Soo Chin Lee, Shuji Ogino, Stephanie Bien, Charles Kooperberg, Christopher Li, Yi Lin, Ross Prentice, Conghui Qu, Stéphane Bézieau, Catherine Tangen, Elaine Mardis, Taiki Yamaji, Norie Sawada, Motoki Iwasaki, Christopher Haiman, Loic Le Marchand, Anna Wu, Chenxu Qu, Caroline McNeil, Gerhard Coetzee, Caroline Hayward, Ian Deary, Sarah Harris, Evropi Theodoratou, Stuart Reid, Marion Walker, Li Yin Ooi, Victor Moreno, Graham Casey, Stephen Gruber, Ian Tomlinson, Wei Zheng, Malcolm Dunlop, Richard Houlston & Ulrike Peters
Nature Genetics