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ORIGINAL RESEARCH article

Front. Genet.
Sec. Human and Medical Genomics
Volume 15 - 2024 | doi: 10.3389/fgene.2024.1425370
This article is part of the Research Topic Biomarkers and Mechanisms of Gastrointestinal Diseases View all articles

Gaining new insights into the etiology of ulcerative colitis through a cross-tissue transcriptome-wide association study

Provisionally accepted
Shijie Ren Shijie Ren 1,2Chaodi Sun Chaodi Sun 2Wenjing Zhai Wenjing Zhai 2Wenli Wei Wenli Wei 2Jianping Liu Jianping Liu 2*
  • 1 Other, Shijiazhuang, China
  • 2 Hebei University of Chinese Medicine, Shijiazhuang, China

The final, formatted version of the article will be published soon.

    Background: Genome-wide association studies (GWASs) have identified 38 loci associated with ulcerative colitis (UC) susceptibility, but the risk genes and their biological mechanisms remained to be comprehensively elucidated. Methods: Multi-marker analysis of genomic annotation (MAGMA) software was used to annotate genes on GWAS summary statistics of UC from FinnGen database. Genetic analysis was performed to identify risk genes. Cross-tissue transcriptome-wide association study (TWAS) using the unified test for molecular signatures (UTMOST) was performed to compare GWAS summary statistics with gene expression matrix (from Genotype-Tissue Expression Project) for data integration. Subsequently, we used FUSION software to select key genes from the individual tissues. Additionally, conditional and joint analysis was conducted to improve our understanding on UC. Fine-mapping of causal gene sets (FOCUS) software was employed to accurately locate risk genes. The results of the four genetic analyses (MAGMA, UTMOST, FUSION and FOCUS) were combined to obtain a set of UC risk genes. Finally, Mendelian randomization (MR) analysis and Bayesian colocalization analysis were conducted to determine the causal relationship between the risk genes and UC. To test the robustness of our findings, the same approaches were taken to verify the GWAS data of UC on IEU. Results: Multiple correction tests screened PIM3 as a risk gene for UC. The results of Bayesian colocalization analysis showed that the posterior probability of hypothesis 4 was 0.997 and 0.954 in the validation dataset. MR was conducted using the inverse variance weighting method and 2 single nucleotide polymorphisms (SNPs, rs28645887 and rs62231924) were included in the analysis (P < 0.001, 95%CI: 1.45-1.89). In the validation dataset, MR result was P < 0.001, 95%CI: 1.19-1.72, indicating a clear causal relationship between PIM3 and UC. Conclusion: Our study validated PIM3 as a key risk gene for UC and its expression level may be related to the risk of UC, providing a novel reference for further improving the current understanding on the genetic structure of UC.

    Keywords: Genetic structure, Pathogenic Mechanism, polymorphism, TWAS, ulcerative colitis

    Received: 29 Apr 2024; Accepted: 25 Jun 2024.

    Copyright: © 2024 Ren, Sun, Zhai, Wei and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jianping Liu, Hebei University of Chinese Medicine, Shijiazhuang, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.