Discovery of common and rare genetic risk variants for colorectal cancer
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2019-01-01
Date Acceptance
2018-10-22
Citation
Nature Genetics, 2019, 51 (1), pp.76-87
ISSN
1061-4036
Publisher
Nature Research
Start Page
76
End Page
87
Journal / Book Title
Nature Genetics
Volume
51
Issue
1
Copyright Statement
© 2019 Springer Nature Publishing AG
Sponsor
Health Research Board - Ireland
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000454108800015&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
HRA_PHS/2011/3
Subjects
Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
GENOME-WIDE ASSOCIATION
SUSCEPTIBILITY LOCI
COLON-CANCER
LYSOPHOSPHATIDIC ACID
QUALITY-CONTROL
IDENTIFIES 6
ORGAN SIZE
METAANALYSIS
EXPRESSION
MUTATIONS
Publication Status
Published
Date Publish Online
2018-12-03