Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort

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.

Fig. 1

Manhattan plot of p-values from logistic regression (with significant principal components and sex as covariates) comparing frequency of exome sequencing common variants in pediatric IBD cases to controls from dbGaP

Fig. 2

Pathway enrichment of the genes annotated to the top 200 most significant common genes tested in our logistic regression

Fig. 3

Manhattan plot of p-values from comparing frequency of exome sequencing rare variants in pediatric IBD cases to ExAC after filtering out sites most significantly different between ExAC and our control data set

Fig. 4

Pathway enrichment of the genes annotated to the top 200 most significant rare variants tested in our rare variant analysis