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

• Type of Material: Article
• Authors: Kelly A. Shaw, Emory University; David Cutler, Emory University; David Okou, Emory University; Anne Dodd, Emory University; Bruce J. Aronow, Cincinnati Children's Hospital Medical Center; Yael Haberman, Cincinnati Children's Hospital Medical Center; Christine Stevens, Broad Institute; Thomas D. Walters, University of Toronto; Anne Griffiths, University of Toronto; Robert N. Baldassano, University of Pennsylvania; Joshua D. Noe, Medical College of Wisconsin; Jeffrey S. Hyams, Connecticut Children’s Medical Center; Wallace V. Crandall, Ohio State University; Barbara S. Kirschner, University of Chicago; Melvin B. Heyman, University of California, San Francisco; Scott Snapper, Children's Hospital Boston; Stephen Guthery, University of Utah; Marla C. Dubinsky, The Mount Sinai Hospital; Jason M. Shapiro, Hasbro Children's Hospital; Anthony R. Otley, Dalhousie University; Mark Daly, Broad Institute; Lee A. Denson, Cincinnati Children's Hospital Medical Center; Subramaniam Kugathasan, Emory University; Michael Zwick, Emory University
• Language: English
• Date: 2018-03-28
• Publisher: Springer Nature [academic journals on nature.com]: Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 The Author(s)
• Final Published Version (URL): http://dx.doi.org/10.1038/s41435-018-0015-2
• Title of Journal or Parent Work: Genes and Immunity
• ISSN: 1466-4879
• Start Page: 1
• End Page: 12
• Grant/Funding Information: K.A.S. received support from BWF training grant ID#1008188 and NIH NRSA F31 DK107229.; This work was supported by NIH R01 DK098231 and the Crohn’s and Colitis Foundation.
• Keywords: genetic variation; disease development; extracellular matrix; Crohn's disease; exome sequencing; pediatric inflammatory bowel disease; pediatric cohorts; disease variance; ulcerative colitis
• Research Categories: Biology, Virology

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.