Discovery of common and rare genetic risk variants for colorectal cancer.
Abstact
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<sup>-8</sup>, 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.
Authors
- Abecasis GR
- Albanes D
- Alonso MH
- Anderson K
- Arnau-Collell C
- Arndt V
- Bamia C
- Banbury BL
- Baron JA
- Bassik MC
- Berndt SI
- Bien SA
- Bishop DT
- Boehm J
- Boeing H
- Brenner H
- Brezina S
- Buch S
- Buchanan DD
- Burnett-Hartman A
- Butterbach K
- Bézieau S
- Caan BJ
- Campbell PT
- Carlson CS
- Casey G
- Castellví-Bel S
- Chan AT
- Chang-Claude J
- Chanock SJ
- Chen S
- Chirlaque MD
- Cho SH
- Connolly CM
- Conti DV
- Cross AJ
- Cuk K
- Curtis KR
- Doheny KF
- Duggan D
- Easton DF
- Edlund CK
- 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
- Greenside P
- Grove JS
- Gruber SB
- Gsur A
- Gunter MJ
- Haile RW
- Hampe J
- Hampel H
- Harlid S
- Harrison TA
- Hayes RB
- Hofer P
- Hoffmeister M
- Hopper JL
- Hsu L
- Hsu WL
- Huang WY
- Hudson TJ
- Hunter DJ
- Huyghe JR
- Ibañez-Sanz G
- Idos GE
- Ingersoll R
- Jackson RD
- Jacobs EJ
- Jenkins MA
- Jeon J
- Joshi AD
- Joshu CE
- Kang HM
- Keku TO
- Key TJ
- Kim HR
- Kobayashi E
- Kolonel LN
- Kooperberg C
- Kundaje A
- Kweon SS
- Kühn T
- Küry S
- Larsson SC
- Laurie CA
- Le Marchand L
- Leal SM
- Lee SC
- Lejbkowicz F
- Lemire M
- Levine DM
- Li CI
- Li L
- Lieb W
- Lin Y
- Lindblom A
- Lindor NM
- Ling H
- Louie TL
- Markowitz SD
- Martín V
- Masala G
- McNeil CE
- Melas M
- Milne RL
- Moreno L
- Moreno V
- Murphy N
- Myte R
- Männistö S
- Naccarati A
- Nelson SC
- Newcomb PA
- Nickerson DA
- Offit K
- Ogino S
- Onland-Moret NC
- Pardini B
- Parfrey PS
- Pearlman R
- Perduca V
- Peters U
- Pharoah PDP
- Pinchev M
- Platz EA
- Potter JD
- Prentice RL
- Pugh E
- Qu C
- Raskin L
- Rennert G
- Rennert HS
- Riboli E
- Rodríguez-Barranco M
- Romm J
- Sakoda LC
- Scacheri PC
- Schafmayer C
- Schmit SL
- Schoen RE
- Schumacher FR
- Seminara D
- Shah M
- Shelford T
- Shin MH
- Shulman K
- Sieri S
- Sinnott-Armstrong NA
- Slattery ML
- Smith JD
- Southey MC
- Stadler ZK
- Stegmaier C
- Su YR
- Tangen CM
- Thibodeau SN
- Thomas DC
- Thomas SS
- Toland AE
- Trichopoulou A
- Ulrich CM
- Van Den Berg DJ
- Van Guelpen B
- Vijai J
- Visvanathan K
- Vodicka P
- Vodickova L
- Vymetalkova V
- Wainberg M
- Weigl K
- Weinstein SJ
- White E
- Win AK
- Wolf CR
- Wolk A
- Woods MO
- Wu AH
- Zaidi SH
- Zanke BW
- Zhang Q
- Zheng W
- de la Chapelle A
- van Duijnhoven FJB
- van Kranen H