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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.

Original publication

DOI

10.1038/s41588-018-0286-6

Type

Journal article

Journal

Nature genetics

Publication Date

01/2019

Volume

51

Pages

76 - 87

Addresses

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Keywords

Humans, Colorectal Neoplasms, Genetic Predisposition to Disease, Risk Factors, Case-Control Studies, Signal Transduction, Genotype, Polymorphism, Single Nucleotide, Aged, Middle Aged, Female, Male, Genome-Wide Association Study, RNA, Long Noncoding