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

Kelly A. Shaw, David J. Cutler, David Okou, Anne Dodd, Bruce J. Aronow, Yael Haberman, Christine Stevens, Thomas D. Walters, Anne Griffiths, Robert N. Baldassano, Joshua D. Noe, Jeffrey S. Hyams, Wallace V. Crandall, Barbara S. Kirschner, Melvin B. Heyman, Scott Snapper, Stephen Guthery, Marla C. Dubinsky, Jason M. Shapiro, Anthony R. OtleyMark Daly, Lee A. Denson, Subra Kugathasan, Michael E. Zwick*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)131-142
Number of pages12
JournalGenes and Immunity
Issue number2
StatePublished - 1 Feb 2019
Externally publishedYes


FundersFunder number
Crohn’s and Colitis Foundation
NIH NRSA F31 DK107229F31 DK107229
National Institutes of HealthR01 DK098231
National Institute of Mental HealthR01MH089004
Burroughs Wellcome Fund1008188


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