Discovery of common and rare genetic risk variants for colorectal cancer

Autoren

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

Jahr

2019

Journal

Nature genetics

Pubmed

30510241

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 x 10(-8), bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Kruppel-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.