Discovery of common and rare genetic risk variants for colorectal cancer Journal Article


Authors: 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.; Anderson, K.; Arnau-Collell, C.; Arndt, V.; Bamia, C.; Banbury, B. L.; Baron, J. A.; Berndt, S. I.; Bézieau, S.; Bishop, D. T.; Boehm, J.; Boeing, H.; Brenner, H.; Brezina, S.; Buch, S.; Buchanan, D. D.; Burnett-Hartman, A.; Butterbach, K.; Caan, B. J.; Campbell, P. T.; Carlson, C. S.; Castellví-Bel, S.; Chan, A. T.; Chang-Claude, J.; Chanock, S. J.; Chirlaque, M. D.; Cho, S. H.; Connolly, C. M.; Cross, A. J.; Cuk, K.; Curtis, K. R.; de la Chapelle, A.; Doheny, K. F.; Duggan, D.; Easton, D. F.; Elias, S. G.; Elliott, F.; English, D. R.; Feskens, E. J. M.; Figueiredo, J. C.; Fischer, R.; FitzGerald, L. M.; Forman, D.; Gala, M.; Gallinger, S.; Gauderman, W. J.; Giles, G. G.; Gillanders, E.; Gong, J.; Goodman, P. J.; Grady, W. M.; Grove, J. S.; Gsur, A.; Gunter, M. J.; Haile, R. W.; Hampe, J.; Hampel, H.; Harlid, S.; Hayes, R. B.; Hofer, P.; Hoffmeister, M.; Hopper, J. L.; Hsu, W. L.; Huang, W. Y.; Hudson, T. J.; Hunter, D. J.; Ibañez-Sanz, G.; Idos, G. E.; Ingersoll, R.; Jackson, R. D.; Jacobs, E. J.; Jenkins, M. A.; Joshi, A. D.; Joshu, C. E.; Keku, T. O.; Key, T. J.; Kim, H. R.; Kobayashi, E.; Kolonel, L. N.; Kooperberg, C.; Kühn, T.; Küry, S.; Kweon, S. S.; Larsson, S. C.; Laurie, C. A.; Le Marchand, L.; Leal, S. M.; Lee, S. C.; Lejbkowicz, F.; Lemire, M.; Li, C. I.; Lieb, W.; Lin, Y.; Lindblom, A.; Lindor, N. M.; Ling, H.; Louie, T. L.; Männistö, S.; Markowitz, S. D.; Martín, V.; Masala, G.; McNeil, C. E.; Melas, M.; Milne, R. L.; Moreno, L.; Murphy, N.; Myte, R.; Naccarati, A.; Newcomb, P. A.; Offit, K.; Ogino, S.; Onland-Moret, N. C.; Pardini, B.; Parfrey, P. S.; Pearlman, R.; Perduca, V.; Pharoah, P. D. P.; Pinchev, M.; Platz, E. A.; Prentice, R. L.; Pugh, E.; Raskin, L.; Rennert, G.; Rennert, H. S.; Riboli, E.; Rodríguez-Barranco, M.; Romm, J.; Sakoda, L. C.; Schafmayer, C.; Schoen, R. E.; Seminara, D.; Shah, M.; Shelford, T.; Shin, M. H.; Shulman, K.; Sieri, S.; Slattery, M. L.; Southey, M. C.; Stadler, Z. K.; Stegmaier, C.; Su, Y. R.; Tangen, C. M.; Thuibodeau, S. N.; Thomas, D. C.; Thomas, S. S.; Toland, A. E.; Trichopoulou, A.; Ulrich, C. M.; Van Den Berg, D. J.; van Duijnhoven, F. J. B.; Van Guelpen, B.; van Kranen, H.; Vijai, J.; Visvanathan, K.; Vodicka, P.; Vodickova, L.; Vymetalkova, V.; Weigl, K.; Weinstein, S. J.; White, E.; Win, A. K.; Wolf, C. R.; Wolk, A.; Woods, M. O.; Wu, A. H.; Zaidi, S. H.; Zanke, B. W.; Zhang, Q.; Zhang, W.; Scacheri, P. C.; Potter, J. D.; Bassik, M. C.; Kundaje, A.; Casey, G.; Moreno, V.; Abecasis, G. R.; Nickerson, D. A.; Gruber, S. B.; Hsu, L.; Peters, U.
Article Title: 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. © 2018, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
Journal Title: Nature Genetics
Volume: 51
Issue: 1
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2019-01-01
Start Page: 76
End Page: 87
Language: English
DOI: 10.1038/s41588-018-0286-6
PROVIDER: scopus
PUBMED: 30510241
DOI/URL:
Notes: Vijai Joseph's first and last names are reversed on the original publication -- Nat. Genet. -- Export Date: 2 January 2019 -- Article -- CODEN: NGENE C2 - 30510241 -- Source: Scopus
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MSK Authors
  1. Kenneth Offit
    494 Offit
  2. Zsofia Kinga Stadler
    139 Stadler
  3. Vijai Joseph
    113 Joseph