Faculty Collaboration Database

Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort. Genes Immun 2019 Feb;20(2):131-142

Date

03/30/2018

Pubmed ID

29593342

Pubmed Central ID

PMC6162182

DOI

10.1038/s41435-018-0015-2

Scopus ID

2-s2.0-85044453960 (requires institutional sign-in at Scopus site)   20 Citations

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.

Author List

Shaw KA, Cutler DJ, Okou D, Dodd A, Aronow BJ, Haberman Y, Stevens C, Walters TD, Griffiths A, Baldassano RN, Noe JD, Hyams JS, Crandall WV, Kirschner BS, Heyman MB, Snapper S, Guthery S, Dubinsky MC, Shapiro JM, Otley AR, Daly M, Denson LA, Kugathasan S, Zwick ME

Author

Joshua D. Noe MD Associate Dean, Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adolescent
Child
Child, Preschool
Female
Genome-Wide Association Study
Humans
Infant
Inflammatory Bowel Diseases
Male
Polymorphism, Genetic