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Author Notes:

Correspondence: Michael E. Zwick, PhD, mzwick@emory.edu, Tel: 404-727-9924

We would like to thank our study participants as well as the providers and facilitators of publicly available data used in this project: the Exome Aggregation Consortium; the NCBI database of genotypes and phenotypes; the Epi4K Gene Discovery in Epilepsy study (NINDS U01-NS077303) and the Epilepsy Genome/Phenome Project (EPGP - NINDS U01-NS053998); and the ARRA Autism Sequencing Collaborative (an ARRA funded research initiative—R01-MH089208, R01-MH089175, R01-MH089025, R01-MH089004, and R01-MH089482).

The authors declare they have no conflicts of interest.


Research Funding:

This work was supported by NIH R01 DK098231 and the Crohn’s and Colitis Foundation.

K.A.S. received support from BWF training grant ID#1008188 and NIH NRSA F31 DK107229.


  • genetic variation
  • pediatric inflammatory bowel disease
  • pediatric cohorts
  • Crohn's disease
  • ulcerative colitis
  • disease variance
  • disease development
  • exome sequencing
  • extracellular matrix

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

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Journal Title:

Genes and Immunity


, Pages 1-12

Type of Work:

Article | Post-print: After Peer 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.

Copyright information:

© 2018 The Author(s)

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