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

Nat Genet
Authors
Jeroen Huyghe
Stephanie Bien
Tabitha Harrison
Hyun Kang
Sai Chen
Stephanie Schmit
David Conti
Conghui Qu
Jihyoun Jeon
Christopher Edlund
Peyton Greenside
Michael Wainberg
Fredrick Schumacher
Joshua Smith
David Levine
Sarah Nelson
Nasa Sinnott-Armstrong
Demetrius Albanes
M Henar Alonso
Kristin Anderson
Coral Arnau-Collell
Volker Arndt
Christina Bamia
Barbara Banbury
John Baron
Sonja Berndt
Stéphane Bezieau
D Timothy Bishop
Juergen Boehm
Heiner Boeing
Hermann Brenner
Stefanie Brezina
Stephan Buch
Daniel Buchanan
Andrea Burnett-Hartman
Katja Butterbach
Bette Caan
Peter Campbell
Christopher Carlson
Sergi Castellví-Bel
Andrew Chan
Jenny Chang-Claude
Stephen Chanock
María-Dolores Chirlaque
Sang Cho
Charles Connolly
Amanda Cross
Katarina Cuk
Keith Curtis
Albert de la Chapelle
Kimberly Doheny
David Duggan
Douglas Easton
Sjoerd Elias
Faye Elliott
Dallas English
Edith Feskens
Jane Figueiredo
Rocky Fischer
Liesel Fitzgerald
David Forman
Manish Gala
Steven Gallinger
W James Gauderman
Graham Giles
Elizabeth Gillanders
Jian Gong
Phyllis Goodman
William Grady
John Grove
Andrea Gsur
Marc Gunter
Robert Haile
Jochen Hampe
Heather Hampel
Sophia Harlid
Richard Hayes
Philipp Hofer
Michael Hoffmeister
John Hopper
Wan-Ling Hsu
Wen-Yi Huang
Thomas Hudson
David Hunter
Gemma Ibañez-Sanz
Gregory Idos
Roxann Ingersoll
Rebecca Jackson
Eric Jacobs
Mark Jenkins
Amit Joshi
Corinne Joshu
Temitope Keku
Timothy Key
Hyeong Kim
Emiko Kobayashi
Laurence Kolonel
Charles Kooperberg
Tilman Kühn
Sébastien Küry
Sun-Seog Kweon
Susanna Larsson
Cecelia Laurie
Loic Le Marchand
Suzanne Leal
Soo Lee
Flavio Lejbkowicz
Mathieu Lemire
Christopher Li
Li Li
Wolfgang Lieb
Yi Lin
Annika Lindblom
Noralane Lindor
Hua Ling
Tin Louie
Satu Männistö
Sanford Markowitz
Vicente Martín
Giovanna Masala
Caroline McNeil
Marilena Melas
Roger Milne
Lorena Moreno
Neil Murphy
Robin Myte
Alessio Naccarati
Polly Newcomb
Kenneth Offit
Shuji Ogino
N Charlotte Onland-Moret
Barbara Pardini
Patrick Parfrey
Rachel Pearlman
Vittorio Perduca
Paul Pharoah
Mila Pinchev
Elizabeth Platz
Ross Prentice
Elizabeth Pugh
Leon Raskin
Gad Rennert
Hedy Rennert
Elio Riboli
Miguel Rodriguez-Barranco
Jane Romm
Lori Sakoda
Clemens Schafmayer
Robert Schoen
Daniela Seminara
Mitul Shah
Tameka Shelford
Min-Ho Shin
Katerina Shulman
Sabina Sieri
Martha Slattery
Melissa Southey
Zsofia Stadler
Christa Stegmaier
Yu-Ru Su
Catherine Tangen
Stephen Thibodeau
Duncan Thomas
Sushma Thomas
Amanda Toland
Antonia Trichopoulou
Cornelia Ulrich
David Van Den Berg
Franzel van Duijnhoven
Bethany Van Guelpen
Henk van Kranen
Joseph Vijai
Kala Visvanathan
Pavel Vodicka
Ludmila Vodickova
Veronika Vymetalkova
Korbinian Weigl
Stephanie Weinstein
Emily White
Aung Win
C Roland Wolf
Alicja Wolk
Michael Woods
Anna Wu
Syed Zaidi
Brent Zanke
Qing Zhang
Wei Zheng
Peter Scacheri
John Potter
Michael Bassik
Anshul Kundaje
Graham Casey
Victor Moreno
Gonçalo Abecasis
Deborah Nickerson
Stephen Gruber
Li Hsu
Ulrike Peters
Keywords
Female
Humans
Male
Aged
Genetic Predisposition to Disease
Genotype
Middle Aged
Signal Transduction
Risk Factors
Genome-Wide Association Study
Polymorphism, Single Nucleotide
Case-Control Studies
RNA, Long Noncoding
Colorectal Neoplasms
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, 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.
Year of Publication
2019
Journal
Nat Genet
Volume
51
Issue
1
Pages
76-87
Date Published
2019 Jan
ISSN
1546-1718
DOI
10.1038/s41588-018-0286-6
PubMed ID
30510241
PubMed Central ID
PMC6358437
Links
Grant list
P30 CA015704 / CA / NCI NIH HHS / United States
K01 DK110267 / DK / NIDDK NIH HHS / United States
P30 DK058404 / DK / NIDDK NIH HHS / United States
U01 CA164930 / CA / NCI NIH HHS / United States
U01 CA074794 / CA / NCI NIH HHS / United States
R01 CA207371 / CA / NCI NIH HHS / United States
P30 CA016058 / CA / NCI NIH HHS / United States
K05 CA152715 / CA / NCI NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
MR/L01629X/1 / MRC_ / Medical Research Council / United Kingdom
P01 CA196569 / CA / NCI NIH HHS / United States
10119 / CRUK_ / Cancer Research UK / United Kingdom
U19 CA148107 / CA / NCI NIH HHS / United States
10589 / CRUK_ / Cancer Research UK / United Kingdom
R01 CA059045 / CA / NCI NIH HHS / United States
R01 CA197350 / CA / NCI NIH HHS / United States
10124 / CRUK_ / Cancer Research UK / United Kingdom
R35 CA197735 / CA / NCI NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R01 CA204279 / CA / NCI NIH HHS / United States
U10 CA037429 / CA / NCI NIH HHS / United States
U01 CA182883 / CA / NCI NIH HHS / United States
R01 CA160356 / CA / NCI NIH HHS / United States
UG1 CA189974 / CA / NCI NIH HHS / United States
R01 CA189184 / CA / NCI NIH HHS / United States
U01 CA137088 / CA / NCI NIH HHS / United States
K23 DK103119 / DK / NIDDK NIH HHS / United States
U24 CA074794 / CA / NCI NIH HHS / United States
R21 CA191312 / CA / NCI NIH HHS / United States
U01 CA206110 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
10822 / CRUK_ / Cancer Research UK / United Kingdom
U01 CA167551 / CA / NCI NIH HHS / United States
U01 CA185094 / CA / NCI NIH HHS / United States
P30 CA014089 / CA / NCI NIH HHS / United States
R01 CA081488 / CA / NCI NIH HHS / United States
R01 CA143237 / CA / NCI NIH HHS / United States
R01 CA201407 / CA / NCI NIH HHS / United States
UM1 CA182883 / CA / NCI NIH HHS / United States
HHSN268201200008I / HL / NHLBI NIH HHS / United States
U01 CA152756 / CA / NCI NIH HHS / United States
R01 CA193677 / CA / NCI NIH HHS / United States

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