Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort
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Updated: Feb 12, 2026
Dynamic Adhesion Assay for the Functional Analysis of Anti-adhesion Therapies in Inflammatory Bowel Disease
Published on: September 20, 2018
Kelly A Shaw1, David J Cutler1, David Okou2
1Department of Human Genetics, Emory University, Atlanta, GA, USA.
Insights
Rare genetic variants contribute to pediatric inflammatory bowel disease (IBD), offering insights beyond common IBD genes. This study analyzed rare variants in pediatric IBD patients, revealing links to immune pathways and extracellular matrix genes.
Area of Science:
- Genetics
- Gastroenterology
- Pediatrics
Background:
- Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), affects approximately 5% of individuals under 20 in the US.
- While over 200 IBD-associated loci are known from genome-wide association studies, they explain limited disease variance.
- Pediatric IBD cohorts offer unique perspectives on the genetic underpinnings of these complex conditions.
Purpose of the Study:
- To investigate the role of rare genetic variants in the development of pediatric IBD.
- To compare exome sequencing data from pediatric IBD patients with publicly available datasets.
Main Methods:
- Exome sequencing of 368 pediatric IBD patients was compared to dbGaP and ExAC data.
- Logistic regression and optimal unified association tests (SKAT-O) were used for variant analysis.
- Pathway enrichment analysis was performed on significant genes.
Main Results:
- Numerous variants overlapped with known IBD-associated genes, such as NOD2.
- Rare variants showed enrichment in CD-associated loci (p=0.009) and suggestive enrichment in neutrophil function genes (p=0.05).
- Immune-related pathways, including cell killing and apoptosis, were implicated, along with extracellular matrix genes.
Conclusions:
- Rare genetic variants play a significant role in pediatric IBD pathogenesis.
- The findings highlight the importance of investigating rare variants to fully understand IBD genetics.
- Immune and extracellular matrix pathways are key areas for future research in pediatric IBD.
Abstract:
In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.
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