Discovery of common and rare genetic risk variants for colorectal cancer.

Author(s): 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,  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 MD,  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 WL,  Huang WY,  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 SS,  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 MH,  Shulman K,  Sieri S,  Slattery ML,  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 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

Journal: Nat Genet

Date: 2019 Jan

Major Program(s) or Research Group(s): PLCO

PubMed ID: 30510241

PMC ID: PMC6358437

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.