Abstract
Background & AimsThe association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease. Here, our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites (ascending, transverse, and descending), (2) to identify expression and splicing quantitative trait loci (QTLs), (3) to find traits for which identified QTLs contribute to single-nucleotide polymorphism (SNP)-based heritability, (4) to propose candidate effector genes, and (5) to provide a web-based visualization resource.MethodsWe collected colonic mucosal biopsy specimens from 485 healthy adults and performed bulk RNA sequencing. We performed genome-wide SNP genotyping from blood leukocytes. Statistical approaches and bioinformatics software were used for QTL identification and downstream analyses.ResultsWe provided a complete quantification of gene expression and alternative splicing across colon subsites and described their differences. We identified thousands of expression and splicing QTLs and defined their enrichment at genome-wide regulatory regions. We found that part of the SNP-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, but also of diseases affecting other tissues, such as psychiatric conditions, can be explained by the identified QTLs. We provided candidate effector genes for multiple phenotypes. Finally, we provided the Colon Transcriptome Explorer web application.ConclusionsWe provide a large characterization of gene expression and splicing across colon subsites. Our findings provide greater etiologic insight into complex traits and diseases influenced by transcriptomic changes in colon tissue.
Highlights
BACKGROUND & AIMSThe association of genetic variation with tissue-specific gene expression and alternative splicing guides functional characterization of complex trait-associated loci and may suggest novel genes implicated in disease
We found that part of the single-nucleotide polymorphism (SNP)-based heritability of diseases affecting colon tissue, such as colorectal cancer and inflammatory bowel disease, and of diseases affecting other tissues, such as psychiatric conditions, 182 Díez-Obrero et al Cellular and Molecular Gastroenterology and Hepatology Vol 12, No 1 can be explained by the identified QTLs
A large public transcriptome data set for non-neoplastic colon tissue from the Genotype-Tissue Expression (GTEx) project included samples collected from the transverse and sigmoid colon of post-mortem subjects and included both mucosa and muscularis propria.[8]
Summary
Our aims were as follows: (1) to generate reference profiles of colon mucosa gene expression and alternative splicing and compare them across colon subsites, (2) to identify expression and splicing. We aimed to identify genes and splicing features that were expressed differentially across colon subsites, situating the transverse colon as an intermediate phenotype
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