Discovery of common and rare genetic risk variants for colorectal cancer

Jeroen R. Huyghe, Stephanie A. Bien, Tabitha A. Harrison, Hyun Min Kang, Sai Chen, Stephanie L. Schmit, David V. Conti, Conghui Qu, Jihyoun Jeon, Christopher K. Edlund, Peyton Greenside, Michael Wainberg, Fredrick R. Schumacher, Joshua D. Smith, David M. Levine, Sarah C. Nelson, Nasa A. Sinnott-Armstrong, Demetrius Albanes, M. Henar Alonso, Kristin AndersonCoral Arnau-Collell, Volker Arndt, Christina Bamia, Barbara L. Banbury, John A. Baron, Sonja I. Berndt, Stéphane Bézieau, D. Timothy Bishop, Juergen Boehm, Heiner Boeing, Hermann Brenner, Stefanie Brezina, Stephan Buch, Daniel D. Buchanan, Andrea Burnett-Hartman, Katja Butterbach, Bette J. Caan, Peter T. Campbell, Christopher S. Carlson, Sergi Castellví-Bel, Andrew T. Chan, Jenny Chang-Claude, Stephen J. Chanock, Maria Dolores Chirlaque, Sang Hee Cho, Charles M. Connolly, Amanda J. Cross, Katarina Cuk, Keith R. Curtis, Albert de la Chapelle, Kimberly F. Doheny, David Duggan, Douglas F. Easton, Sjoerd G. Elias, Faye Elliott, Dallas R. English, Edith J.M. Feskens, Jane C. Figueiredo, Rocky Fischer, Liesel M. FitzGerald, David Forman, Manish Gala, Steven Gallinger, W. James Gauderman, Graham G. Giles, Elizabeth Gillanders, Jian Gong, Phyllis J. Goodman, William M. Grady, John S. Grove, Andrea Gsur, Marc J. Gunter, Robert W. Haile, Jochen Hampe, Heather Hampel, Sophia Harlid, Richard B. Hayes, Philipp Hofer, Michael Hoffmeister, John L. Hopper, Wan Ling Hsu, Wen Yi Huang, Thomas J. Hudson, David J. Hunter, Gemma Ibañez-Sanz, Gregory E. Idos, Roxann Ingersoll, Rebecca D. Jackson, Eric J. Jacobs, Mark A. Jenkins, Amit D. Joshi, Corinne E. Joshu, Temitope O. Keku, Timothy J. Key, Hyeong Rok Kim, Emiko Kobayashi, Laurence N. Kolonel, Charles Kooperberg, Tilman Kühn, Sébastien Küry, Sun Seog Kweon, Susanna C. Larsson, Cecelia A. Laurie, Loic Le Marchand, Suzanne M. Leal, Soo Chin Lee, Flavio Lejbkowicz, Mathieu Lemire, Christopher I. Li, Li Li, Wolfgang Lieb, Yi Lin, Annika Lindblom, Noralane M. Lindor, Hua Ling, Tin L. Louie, Satu Männistö, Sanford D. Markowitz, Vicente Martín, Giovanna Masala, Caroline E. McNeil, Marilena Melas, Roger L. Milne, Lorena Moreno, Neil Murphy, Robin Myte, Alessio Naccarati, Polly A. Newcomb, Kenneth Offit, Shuji Ogino, N. Charlotte Onland-Moret, Barbara Pardini, Patrick S. Parfrey, Rachel Pearlman, Vittorio Perduca, Paul D.P. Pharoah, Mila Pinchev, Elizabeth A. Platz, Ross L. Prentice, Elizabeth Pugh, Leon Raskin, Gad Rennert, Hedy S. Rennert, Elio Riboli, Miguel Rodríguez-Barranco, Jane Romm, Lori C. Sakoda, Clemens Schafmayer, Robert E. Schoen, Daniela Seminara, Mitul Shah, Tameka Shelford, Min Ho Shin, Katerina Shulman, Sabina Sieri, Martha L. Slattery, Melissa C. Southey, Zsofia K. Stadler, Christa Stegmaier, Yu Ru Su, Catherine M. Tangen, Stephen N. Thibodeau, Duncan C. Thomas, Sushma S. Thomas, Amanda E. Toland, Antonia Trichopoulou, Cornelia M. Ulrich, David J. Van Den Berg, Franzel J.B. van Duijnhoven, Bethany Van Guelpen, Henk van Kranen, Joseph Vijai, Kala Visvanathan, Pavel Vodicka, Ludmila Vodickova, Veronika Vymetalkova, Korbinian Weigl, Stephanie J. Weinstein, Emily White, Aung Ko Win, C. Roland Wolf, Alicja Wolk, Michael O. Woods, Anna H. Wu, Syed H. Zaidi, Brent W. Zanke, Qing Zhang, Wei Zheng, Peter C. Scacheri, John D. Potter, Michael C. Bassik, Anshul Kundaje, Graham Casey, Victor Moreno, Goncalo R. Abecasis, Deborah A. Nickerson, Stephen B. Gruber, Li Hsu, Ulrike Peters

Research output: Contribution to journalArticle

48 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)76-87
Number of pages12
JournalNature Genetics
Volume51
Issue number1
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Genetics

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    Huyghe, J. R., Bien, S. A., Harrison, T. A., Kang, H. M., Chen, S., Schmit, S. L., Conti, D. V., Qu, C., Jeon, J., Edlund, C. K., Greenside, P., Wainberg, M., Schumacher, F. R., Smith, J. D., Levine, D. M., Nelson, S. C., Sinnott-Armstrong, N. A., Albanes, D., Alonso, M. H., ... Peters, U. (2019). Discovery of common and rare genetic risk variants for colorectal cancer. Nature Genetics, 51(1), 76-87. https://doi.org/10.1038/s41588-018-0286-6