title: cis-Expression QTL analysis of established colorectal cancer risk variants in colon tumors and adjacent normal tissue.
abstract: Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent normal colon tissues were used for genome-wide SNP and gene expression profiling. We found that three risk variants (rs10795668, rs4444235 and rs9929218, using near perfect proxies rs706771, rs11623717 and rs2059252, respectively) were significantly associated (FDR q-value ≤0.05) with expression levels of nearby genes (<2 Mb up- or down-stream). We observed an association between the low colorectal cancer risk allele (A) for rs10795668 at 10p14 and increased expression of ATP5C1 (q = 0.024) and between the colorectal cancer high risk allele (C) for rs4444235 at 14q22.2 and increased expression of DLGAP5 (q = 0.041), both in tumor samples. The colorectal cancer low risk allele (A) for rs9929218 at 16q22.1 was associated with a significant decrease in expression of both NOL3 (q = 0.017) and DDX28 (q = 0.046) in the adjacent normal colon tissue samples. Of the four genes, DLGAP5 and NOL3 have been previously reported to play a role in colon carcinogenesis and ATP5C1 and DDX28 are mitochondrial proteins involved in cellular metabolism and division, respectively. The combination of GWAS findings, prior functional studies, and the cis-eQTL analyses described here suggest putative functional activities for three of the colorectal cancer GWAS identified risk loci as regulating the expression of neighboring genes.
authors.affiliation: Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America. lloo@cc.hawaii.edu
authors.forename: Lenora W M
authors.initials: LW
authors.lastname: Loo
authors.forename: Iona
authors.initials: I
authors.lastname: Cheng
authors.forename: Maarit
authors.initials: M
authors.lastname: Tiirikainen
authors.forename: Annette
authors.initials: A
authors.lastname: Lum-Jones
authors.forename: Ann
authors.initials: A
authors.lastname: Seifried
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Dunklee
authors.forename: James M
authors.initials: JM
authors.lastname: Church
authors.forename: Robert
authors.initials: R
authors.lastname: Gryfe
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Robert W
authors.initials: RW
authors.lastname: Haile
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: David J
authors.initials: DJ
authors.lastname: Duggan
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.forename: Graham
authors.initials: G
authors.lastname: Casey
authors.forename: Loïc
authors.initials: L
authors.lastname: Le Marchand
mesh_terms: D003106:Colon / Q000473:pathology*; D015179:Colorectal Neoplasms / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D040641:Quantitative Trait Loci / Q000235:genetics*; D012307:Risk Factors