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. Genome-wide association analyses based on whole-genome sequencing and imputation identify 40 new risk variants for colorectal cancer, including a strongly protective low-frequency variant at CHD1 and loci implicating signaling and immune function in disease etiology.
Discovery of common and rare genetic risk variants for colorectal cancer
J. Huyghe,Stephanie A. Bien,T. Harrison,H. Kang,Sai Chen,S. Schmit,D. Conti,C. Qu,Jihyoun Jeon,C. Edlund,Peyton Greenside,Michael Wainberg,F. Schumacher,Joshua D. Smith,D. Levine,Sarah C. Nelson,Nasa Sinnott-Armstrong,D. Albanes,M. Alonso,K. Anderson,C. Arnau-Collell,V. Arndt,C. Bamia,B. Banbury,J. Baron,S. Berndt,S. Bézieau,D. Bishop,J. Boehm,H. Boeing,H. Brenner,S. Brezina,S. Buch,D. Buchanan,A. Burnett-Hartman,Katja Butterbach,B. Caan,P. Campbell,C. Carlson,S. Castellví-Bel,A. Chan,J. Chang-Claude,S. Chanock,M. Chirlaque,Sang‐Hee Cho,C. Connolly,A. Cross,Katarina Ćuk,Keith R Curtis,A. de la Chapelle,K. Doheny,D. Duggan,D. Easton,S. Elias,F. Elliott,D. English,E. Feskens,J. Figueiredo,Rocky Fischer,L. FitzGerald,D. Forman,M. Gala,S. Gallinger,W. Gauderman,G. Giles,E. Gillanders,Jian Gong,P. Goodman,W. Grady,J. Grove,A. Gsur,M. Gunter,R. Haile,J. Hampe,H. Hampel,Sophia Harlid,R. Hayes,P. Hofer,M. Hoffmeister,J. Hopper,W. Hsu,Wen-Yi Huang,T. Hudson,D. Hunter,G. Ibáñez‐Sanz,Gregory E. Idos,R. Ingersoll,R. Jackson,E. Jacobs,M. Jenkins,A. Joshi,C. Joshu,T. Keku,T. Key,H. Kim,Emiko Kobayashi,L. Kolonel,C. Kooperberg,T. Kühn,S. Küry,S. Kweon,S. Larsson,C. Laurie,L. Le Marchand,S. Leal,S. C. Lee,F. Lejbkowicz,M. Lemire,Christopher I. Li,Li Li,W. Lieb,Yi Lin,A. Lindblom,N. Lindor,H. Ling,T. Louie,S. Männistö,S. Markowitz,V. Martín,G. Masala,C. McNeil,Marilena Melas,R. Milne,Lorena Moreno,N. Murphy,Robin Myte,A. Naccarati,P. Newcomb,K. Offit,S. Ogino,N. Onland-Moret,B. Pardini,P. Parfrey,R. Pearlman,Vittorio Perduca,P. Pharoah,M. Pinchev,E. Platz,R. Prentice,E. Pugh,L. Raskin,G. Rennert,H. Rennert,E. Riboli,M. Rodríguez-Barranco,Jane M. Romm,L. Sakoda,C. Schafmayer,R. Schoen,D. Seminara,M. Shah,T. Shelford,M. Shin,K. Shulman,S. Sieri,M. Slattery,M. Southey,Z. Stadler,C. Stegmaier,Yu-Ru Su,C. Tangen,S. Thibodeau,Duncan C. Thomas,Sushma S. Thomas,A. Toland,A. Trichopoulou,C. Ulrich,D. J. Van Den Berg,F. V. van Duijnhoven,B. van Guelpen,H. V. van Kranen,J. Vijai,K. Visvanathan,P. Vodicka,L. Vodičková,Veronika Vymetálková,K. Weigl,S. Weinstein,E. White,Aung Ko Win,C. Wolf,A. Wolk,M. Woods,A. Wu,Syed H Zaidi,B. Zanke,Qing Zhang,W. Zheng,P. Scacheri,J. Potter,M. Bassik,Anshul B Kundaje,G. Casey,V. Moreno,G. Abecasis,D. Nickerson,S. Gruber,L. Hsu,U. Peters
Published 2018 in Nature Genetics
ABSTRACT
PUBLICATION RECORD
- Publication year
2018
- Venue
Nature Genetics
- Publication date
2018-10-24
- Fields of study
Biology, Medicine
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