In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants

Abstract Background Genome-wide association studies have identified 55 genetic variants associated with colorectal cancer risk to date. However, potential causal genes and pathways regulated by these risk variants remain to be characterized. Therefore, we performed gene ontology enrichment and pathw...

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Main Authors: Lenora W. M. Loo, Mathieu Lemire, Loïc Le Marchand
Format: Article
Language:English
Published: BMC 2017-05-01
Series:BMC Genomics
Subjects:
Online Access:http://link.springer.com/article/10.1186/s12864-017-3750-2
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author Lenora W. M. Loo
Mathieu Lemire
Loïc Le Marchand
author_facet Lenora W. M. Loo
Mathieu Lemire
Loïc Le Marchand
author_sort Lenora W. M. Loo
collection DOAJ
description Abstract Background Genome-wide association studies have identified 55 genetic variants associated with colorectal cancer risk to date. However, potential causal genes and pathways regulated by these risk variants remain to be characterized. Therefore, we performed gene ontology enrichment and pathway analyses to determine if there was an enrichment of genes in proximity to the colorectal cancer risk variants that could further elucidate the probable causal genes and pathways involved in colorectal cancer biology. Results For the 65 unique genes that either contained, or were immediately neighboring up- and downstream, of these variants there was a significant enrichment for the KEGG pathway, Pathways in Cancer (p-value = 2.67 × 10−5) and an enrichment for multiple biological processes (FDR < 0.05), such as cell junction organization, tissue morphogenesis, regulation of SMAD protein phosphorylation, and odontogenesis identified through Gene Ontology analysis. To identify potential causal genes, we conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using gene expression and genotype data from the Genotype-Tissue Expression (GTEx) Project portal in normal sigmoid (n = 124) and transverse (n = 169) colon tissue. In addition, we also did a cis-eQTL analysis on colorectal tumor tissue (n = 147) from The Cancer Genome Atlas (TCGA). We identified two risk alleles that were significant cis-eQTLs for FADS2 (rs1535) and COLCA1 and 2 (rs3802842) genes in the normal transverse colon tissue and two risk alleles that were significant cis-eQTLs for the CABLES2 (rs2427308) and LIPG (rs7229639) genes in the normal sigmoid colon tissue, but not tumor tissue. Conclusions Our data reaffirm the potential to identify an enrichment for biological processes and candidate causal genes based on expression profiles correlated with genetic risk alleles of colorectal cancer, however, the identification of these significant cis-eQTLs is context and tissue specific.
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spelling doaj.art-5b255c4fd1cc475a91b362e0163e83492022-12-21T19:18:39ZengBMCBMC Genomics1471-21642017-05-0118111410.1186/s12864-017-3750-2In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variantsLenora W. M. Loo0Mathieu Lemire1Loïc Le Marchand2Cancer Epidemiology Program, University of Hawaii Cancer CenterOntario Institute for Cancer Research, MaRS Centre, 661 University AvenueCancer Epidemiology Program, University of Hawaii Cancer CenterAbstract Background Genome-wide association studies have identified 55 genetic variants associated with colorectal cancer risk to date. However, potential causal genes and pathways regulated by these risk variants remain to be characterized. Therefore, we performed gene ontology enrichment and pathway analyses to determine if there was an enrichment of genes in proximity to the colorectal cancer risk variants that could further elucidate the probable causal genes and pathways involved in colorectal cancer biology. Results For the 65 unique genes that either contained, or were immediately neighboring up- and downstream, of these variants there was a significant enrichment for the KEGG pathway, Pathways in Cancer (p-value = 2.67 × 10−5) and an enrichment for multiple biological processes (FDR < 0.05), such as cell junction organization, tissue morphogenesis, regulation of SMAD protein phosphorylation, and odontogenesis identified through Gene Ontology analysis. To identify potential causal genes, we conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using gene expression and genotype data from the Genotype-Tissue Expression (GTEx) Project portal in normal sigmoid (n = 124) and transverse (n = 169) colon tissue. In addition, we also did a cis-eQTL analysis on colorectal tumor tissue (n = 147) from The Cancer Genome Atlas (TCGA). We identified two risk alleles that were significant cis-eQTLs for FADS2 (rs1535) and COLCA1 and 2 (rs3802842) genes in the normal transverse colon tissue and two risk alleles that were significant cis-eQTLs for the CABLES2 (rs2427308) and LIPG (rs7229639) genes in the normal sigmoid colon tissue, but not tumor tissue. Conclusions Our data reaffirm the potential to identify an enrichment for biological processes and candidate causal genes based on expression profiles correlated with genetic risk alleles of colorectal cancer, however, the identification of these significant cis-eQTLs is context and tissue specific.http://link.springer.com/article/10.1186/s12864-017-3750-2Colorectal cancereQTLRisk variantGene expression
spellingShingle Lenora W. M. Loo
Mathieu Lemire
Loïc Le Marchand
In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants
BMC Genomics
Colorectal cancer
eQTL
Risk variant
Gene expression
title In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants
title_full In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants
title_fullStr In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants
title_full_unstemmed In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants
title_short In silico pathway analysis and tissue specific cis-eQTL for colorectal cancer GWAS risk variants
title_sort in silico pathway analysis and tissue specific cis eqtl for colorectal cancer gwas risk variants
topic Colorectal cancer
eQTL
Risk variant
Gene expression
url http://link.springer.com/article/10.1186/s12864-017-3750-2
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