The genetic regulation of the gastric transcriptome is associated with metabolic and obesity-related traits and diseases

• Published in: Physiological genomics Vol. 56; no. 5; pp. 384 - 396
• Main Authors: Koebbe, Laura L, Hess, Timo, Giel, Ann-Sophie, Bigge, Jessica, Gehlen, Jan, Schueller, Vitalia, Geppert, Michael, Dumoulin, Franz Ludwig, Heller, Joerg, Schepke, Michael, Plaßmann, Dominik, Vieth, Michael, Venerito, Marino, Schumacher, Johannes, Maj, Carlo
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.05.2024
• Subjects: Biopsy; Body composition; Gene expression; Gene Expression Regulation; Gene polymorphism; Gene regulation; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Glucose metabolism; Heritability; Humans; Metabolism; Mucosa; Obesity; Obesity - genetics; Physiology; Polymorphism, Single Nucleotide - genetics; Protein turnover; Quantitative trait loci; Single-nucleotide polymorphism; Stomach; Transcriptome - genetics; Transcriptomes; expression quantitative trait loci; metabolism; stomach; gene expression
• ISSN: 1094-8341; 1531-2267; 1531-2267
• DOI: 10.1152/physiolgenomics.00120.2023

Tissue-specific gene expression and gene regulation lead to a better understanding of tissue-specific physiology and pathophysiology. We analyzed the transcriptome and genetic regulatory profiles of two distinct gastric sites, corpus and antrum, to identify tissue-specific gene expression and its regulation. Gastric corpus and antrum mucosa biopsies were collected during routine gastroscopies from up to 431 healthy individuals. We obtained genotype and transcriptome data and performed transcriptome profiling and expression quantitative trait locus (eQTL) studies. We further used data from genome-wide association studies (GWAS) of various diseases and traits to partition their heritability and to perform transcriptome-wide association studies (TWAS). The transcriptome data from corpus and antral mucosa highlights the heterogeneity of gene expression in the stomach. We identified enriched pathways revealing distinct and common physiological processes in gastric corpus and antrum. Furthermore, we found an enrichment of the single nucleotide polymorphism (SNP)-based heritability of metabolic, obesity-related, and cardiovascular traits and diseases by considering corpus- and antrum-specifically expressed genes. Particularly, we could prioritize gastric-specific candidate genes for multiple metabolic traits, like which is involved in glucose metabolism, which contributes to purine and protein metabolism or being a regulator of weight and body composition. Our findings show that gastric corpus and antrum vary in their transcriptome and genetic regulatory profiles indicating physiological differences which are mostly related to digestion and epithelial protection. Moreover, our findings demonstrate that the genetic regulation of the gastric transcriptome is linked to biological mechanisms associated with metabolic, obesity-related, and cardiovascular traits and diseases. We analyzed the transcriptomes and genetic regulatory profiles of gastric corpus and for the first time also of antrum mucosa in 431 healthy individuals. Through tissue-specific gene expression and eQTL analyses, we uncovered unique and common physiological processes across both primary gastric sites. Notably, our findings reveal that stomach-specific eQTLs are enriched in loci associated with metabolic traits and diseases, highlighting the pivotal role of gene expression regulation in gastric physiology and potential pathophysiology.