Discovery of common and rare genetic risk variants for colorectal cancer

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.

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Item Type:	Article
Authors/Creators:	Huyghe, JR Bien, SA Harrison, TA Kang, HM Chen, S Schmit, SL Conti, DV Qu, C Jeon, J Edlund, CK Greenside, P Wainberg, M Schumacher, FR Smith, JD Levine, DM Nelson, SC Sinnott-Armstrong, NA Albanes, D Alonso, MH Anderson, K Arnau-Collell, C Arndt, V Bamia, C Banbury, BL Baron, JA Berndt, SI Bézieau, S Bishop, DT https://orcid.org/0000-0002-8752-8785 Boehm, J Boeing, H Brenner, H Brezina, S Buch, S Buchanan, DD Burnett-Hartman, A Butterbach, K Caan, BJ Campbell, PT Carlson, CS Castellví-Bel, S Chan, AT Chang-Claude, J Chanock, SJ Chirlaque, M-D Cho, SH Connolly, CM Cross, AJ Cuk, K Curtis, KR de la Chapelle, A Doheny, KF Duggan, D Easton, DF Elias, SG Elliott, F English, DR Feskens, EJM Figueiredo, JC Fischer, R FitzGerald, LM Forman, D Gala, M Gallinger, S Gauderman, WJ Giles, GG Gillanders, E Gong, J Goodman, PJ Grady, WM Grove, JS Gsur, A Gunter, MJ Haile, RW Hampe, J Hampel, H Harlid, S Hayes, RB Hofer, P Hoffmeister, M Hopper, JL Hsu, W-L Huang, W-Y Hudson, TJ Hunter, DJ Ibañez-Sanz, G Idos, GE Ingersoll, R Jackson, RD Jacobs, EJ Jenkins, MA Joshi, AD Joshu, CE Keku, TO Key, TJ Kim, HR Kobayashi, E Kolonel, LN Kooperberg, C Kühn, T Küry, S Kweon, S-S Larsson, SC Laurie, CA Le Marchand, L Leal, SM Lee, SC Lejbkowicz, F Lemire, M Li, CI Li, L Lieb, W Lin, Y Lindblom, A Lindor, NM Ling, H Louie, TL Männistö, S Markowitz, SD Martín, V Masala, G McNeil, CE Melas, M Milne, RL Moreno, L Murphy, N Myte, R Naccarati, A Newcomb, PA Offit, K Ogino, S Onland-Moret, NC Pardini, B Parfrey, PS Pearlman, R Perduca, V Pharoah, PDP Pinchev, M Platz, EA Prentice, RL Pugh, E Raskin, L Rennert, G Rennert, HS Riboli, E Rodríguez-Barranco, M Romm, J Sakoda, LC Schafmayer, C Schoen, RE Seminara, D Shah, M Shelford, T Shin, M-H Shulman, K Sieri, S Slattery, ML Southey, MC Stadler, ZK Stegmaier, C Su, Y-R Tangen, CM Thibodeau, SN Thomas, DC Thomas, SS Toland, AE Trichopoulou, A Ulrich, CM Van den Berg, DJ van Duijnhoven, FJB Van Guelpen, B van Kranen, H Vijai, J Visvanathan, K Vodicka, P Vodickova, L Vymetalkova, V Weigl, K Weinstein, SJ White, E Win, AK Wolf, CR Wolk, A Woods, MO Wu, AH Zaidi, SH Zanke, BW Zhang, Q Zheng, W Scacheri, PC Potter, JD Bassik, MC Kundaje, A Casey, G Moreno, V Abecasis, GR Nickerson, DA Gruber, SB Hsu, L Peters, U
Copyright, Publisher and Additional Information:	© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2018. This is an author produced version of a paper published in Nature Genetics. Uploaded in accordance with the publisher's self-archiving policy. https://doi.org/10.1038/s41588-018-0286-6.
Dates:	Accepted: 22 October 2018 Published (online): 3 December 2018 Published: 1 January 2019
Institution:	The University of Leeds
Academic Units:	The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds)
Depositing User:	Symplectic Publications
Date Deposited:	14 Feb 2019 10:17
Last Modified:	03 Jun 2019 00:43
Status:	Published
Publisher:	Nature Research
Identification Number:	10.1038/s41588-018-0286-6
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:142531

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Discovery of common and rare genetic risk variants for colorectal cancer

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