An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn's Disease in Japanese Populations

Sci Rep. 2020 Jun 24;10(1):10236. doi: 10.1038/s41598-020-66951-5.

Abstract

Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Case-Control Studies
  • Crohn Disease / genetics*
  • DNA-Binding Proteins / genetics
  • Female
  • Gene Expression Profiling / methods*
  • Gene Expression Regulation
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods*
  • Humans
  • Japan
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Quantitative Trait Loci*
  • Sequence Analysis, RNA
  • T-Lymphocyte Subsets / metabolism
  • Tenascin / genetics
  • Transcription Factors / genetics
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics
  • Young Adult

Substances

  • DNA-Binding Proteins
  • TNFSF15 protein, human
  • TNXA protein, human
  • Tenascin
  • Transcription Factors
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • ZNF713 protein, human