Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn's disease in a Chinese family study

PLoS One. 2014 Jun 17;9(6):e99807. doi: 10.1371/journal.pone.0099807. eCollection 2014.

Abstract

Background: Genetic variants make some contributions to inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). More than 100 susceptibility loci were identified in Western IBD studies, but susceptibility gene has not been found in Chinese IBD patients till now. Sequencing of individuals with an IBD family history is a powerful approach toward our understanding of the genetics and pathogenesis of IBD. The aim of this study, which focuses on a Han Chinese CD family, is to identify high-risk variants and potentially novel loci using whole exome sequencing technique.

Methods: Exome sequence data from 4 individuals belonging to a same family were analyzed using bioinformatics methods to narrow down the variants associated with CD. The potential risk genes were further analyzed by genotyping and Sanger sequencing in family members, additional 401 healthy controls (HC), 278 sporadic CD patients, 123 UC cases, a pair of monozygotic CD twins and another Chinese CD family.

Results: From the CD family in which the father and daughter were affected, we identified a novel single nucleotide variant (SNV) c.374T>C (p.I125T) in exon 4 of discs large homolog 1 (DLG1), a gene has been reported to play multiple roles in cell proliferation, T cell polarity and T cell receptor signaling. After genotyping among case and controls, a PLINK analysis showed the variant was of significance (P<0.05). 4 CD patients of the other Chinese family bore another non-synonymous variant c.833G>A (p.R278Q) in exon 9 of DLG1.

Conclusions: We have discovered novel genetic variants in the coding regions of DLG1 gene, the results support that DLG1 is a novel potential susceptibility gene for CD in Chinese patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adolescent
  • Adult
  • Base Sequence
  • Case-Control Studies
  • China
  • Crohn Disease / genetics*
  • DNA Mutational Analysis
  • Discs Large Homolog 1 Protein
  • Exome*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Humans
  • INDEL Mutation
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Young Adult

Substances

  • Adaptor Proteins, Signal Transducing
  • DLG1 protein, human
  • Discs Large Homolog 1 Protein
  • Membrane Proteins

Grants and funding

The study was supported by the Hubei Clinical Center and Key Laboratory of Intestinal and Colorectal Diseases, the Natural Science Foundation of China (No. 81070280) and a grant from the Ministry of Public Health of China (201002020). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.