Genetic Effects on Transcriptome Profiles in Colon Epithelium Provide Functional Insights for Genetic Risk Loci

Abstract

Colon biopsies from superficial mucosa Gene expression and alternative splicing DNA genotyping eQTLs and sQTLs Blood samples Colon Transcriptome Explorer Enrichment at regulatory regions and trait and diseaseassociated loci Differential expression between colon subsites …ACTGCATGCTACC… SUMMARYWe profiled gene expression and alternative splicing of nonneoplastic colon from biopsy specimens from 445 healthy individuals. We showed that single-nucleotide polymorphisms associated with these profiles are enriched in disease-associated loci, including colorectal cancer and inflammatory bowel disease. BACKGROUND & AIMS:The 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. METHODS:We 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. RESULTS:We 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

Novel insights into the molecular mechanisms underlying risk of colorectal cancer from smoking and red/processed meat carcinogens by modeling exposure in normal colon organoids

“…BarcUVa-Seq data was processed as in the original study [ 16 ]. For the purpose of this study, additional epidemiologic data were collected.…”

“…Raw data generated for this manuscript has been uploaded to Gene Expression Omnibus and is available for download using accession number: GSE174650. Details for access for BarcUVa-Seq can be found in the original manuscript publication [ 16 ].…”

“…We observed a robust transcriptomic response in carcinogens exposed colon organoids that revealed selective changes in cell composition. We replicated a number of these differences in transcription in normal mucosal biopsies derived from current and never smokers using the University of Barcelona and University of Virginia RNA sequencing (BarcUVa-Seq) cohort [ 16 ]. Finally, we performed the first weighted gene co-expression network analysis (WGCNA) of colon organoids treated with carcinogens.…”

The Colon Transcriptome Explorer (CoTrEx) 2.0: a Reference Web-Based Resource for Exploring Population-Based Normal Colon Gene Expression

“…Also, the gene expression prediction models can be downloaded from the Prediction models tab, which are useful for investigators interested in performing TWAS and nominating candidate susceptibility genes for a phenotype of interest. A list of complex traits and diseases for which the gene expression prediction models provided in CoTrEx 2.0 are relevant for TWAS is provided elsewhere [1]. Future developments of CoTrEx 2.0 would include additional QTL sets generated, such as regulatory QTLs, associated with changes in interactions between genes.…”

“…The expression profiles and their association statistics with germline genetic variants, i.e. e/sQTLs, were recently reported and included in the initial version of the Colon Transcriptome Explorer (CoTrEx) [1]. Additionally, the Genotype-Tissue Expression (GTEx) project provided normal colon e/sQTLs from transverse (N=368) and sigmoid (N=318) colon samples from corpses [2].…”