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Characterization of expression quantitative trait loci in the human colon.

ABSTRACT: BACKGROUND:Many genetic risk loci have been identified for inflammatory bowel disease and colorectal cancer; however, identifying the causal genes for each association signal remains a challenge. Expression quantitative trait loci (eQTL) studies have identified common variants that induce differential gene expression and eQTLs can be cross-referenced with disease association signals for gene prioritization. However, the genetics of gene expression are highly tissue-specific, and further eQTL datasets from primary tissues are needed. METHODS:We have conducted an eQTL discovery study using tissue extracted endoscopically from the terminal ileum and 4 colonic locations of non-inflamed bowel from 65 controls and patients with quiescent inflammatory bowel disease. A genome-wide cis-eQTL analysis was performed on >3,600,000 variants and 13,558 expressed probes. RESULTS:We identified 1312 independent eQTLs associated with the differential expression of 1222 genes in rectal mucosa. One hundred seventy-one, 211, 168, and 102 independent eQTLs were identified in the sigmoid, descending colon, ascending colon, and terminal ileum, respectively. Twenty-six percent of genes with rectal eQTLs were novel and unique compared with 7 published eQTL datasets. Rectal eQTLs were significantly enriched for genes expressed in the colon. Examining 163 inflammatory bowel disease risk loci identified 11 tag single-nucleotide polymorphisms that were rectal eQTLs. A colorectal cancer locus at 11q23 contained a rectal eQTL for COLCA2, a protein implicated in colon cancer pathogenesis. CONCLUSIONS:This study defines a catalog of ileal and colonic eQTLs. Our data reaffirm the tissue specificity of eQTLs and support the notion that identification of functional variants in relevant tissue can be effective in fine-mapping genetic risk loci.

SUBMITTER: Singh T

PROVIDER: S-EPMC4345969 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Characterization of expression quantitative trait loci in the human colon.

Singh Tarjinder T Levine Adam P AP Smith Philip J PJ Smith Andrew M AM Segal Anthony W AW Barrett Jeffrey C JC

Inflammatory bowel diseases 20150201 2

<h4>Background</h4>Many genetic risk loci have been identified for inflammatory bowel disease and colorectal cancer; however, identifying the causal genes for each association signal remains a challenge. Expression quantitative trait loci (eQTL) studies have identified common variants that induce differential gene expression and eQTLs can be cross-referenced with disease association signals for gene prioritization. However, the genetics of gene expression are highly tissue-specific, and further ...[more]

PMID: 25569741

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Project description:Genetic dissection of the S rat genome has provided strong evidence for the presence of two interacting blood pressure (BP) quantitative trait loci (QTLs), termed QTL1 and QTL2, on rat chromosome 5. However, the identities of the underlying interacting genetic factors remain unknown. Further experiments targeted to identify the interacting genetic factors by the substitution mapping approach alone are difficult because of the interdependency of natural recombinations to occur at the two QTLs. We hypothesized that the interacting genetic factors underlying these two QTLs may interact at the level of gene transcription and thereby represent expression QTLs (eQTLs). To detect these interacting eQTLs, a custom QTL chip containing the annotated genes within QTL1 and QTL2 was developed and used to conduct a transcriptional profiling study of S and two congenic strains that retain either one or both the QTLs. The results uncovered an interaction between two transcription factors, DMRTA2 and NFIA. Further, the âbiological signatureâ elicited by these two transcription factors was differential between the congenic strain that retained LEW alleles at both QTL1 and 2 compared to the congenic strain that retained LEW alleles at QTL1 alone. A network of transcription factors potentially affecting BP could be traced, lending support to our hypothesis. Pairs of Cy5 and Cy3 labeled targets were co-hybridized onto either a custom long oligonucleotide microarray for the interrogation of 231 genes encompassed by QTL1 and QTL2, or a TIGR rat cDNA array consisting of 26,401 probe elements representing 20,465 unique non-QTL genes. A âflip-dyeâ or âbalanced blockâ design was used as the experimental method of choice to account for potential dye-bias labeling effects. Six âbalanced blockâ normalized files are submitted for the long oligonucleotide array interrogating the hearts from S versus S.LEW(5)x6x9 animals, fourteen âflip-dyeâ hybridizations are submitted for the cDNA array interrogating the hearts from S versus S.LEW(5)x6x9 animals, and twelve âflip-dyeâ hybridizations are submitted for the cDNA array interrogating the hearts from S versus S.LEW(5)x6x11 animals. GPR and MEV files cannot be located.

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Characterization of expression quantitative trait loci in the human colon.

Publications

Characterization of expression quantitative trait loci in the human colon.

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