Author information

1 Department of Human Genetics, Emory University, Atlanta, GA, USA.

2 Department of Pediatrics, Emory University, Atlanta, GA, USA.

3 Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

4 Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

5 Broad Institute of MIT and Harvard, Cambridge, MA, USA.

6 Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.

7 Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

8 Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA.

9 Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA.

10 Department of Pediatric Gastroenterology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.

11 Department of Pediatrics, The University of Chicago Comer Children's Hospital, Chicago, IL, USA.

12 Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA.

13 Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.

14 Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.

15 Department of Pediatrics, Mount Sinai Hospital, New York, NY, USA.

16 Department of Pediatrics, Hasbro Children's Hospital, Providence, RI, USA.

17 Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.

18 Department of Human Genetics, Emory University, Atlanta, GA, USA. mzwick@emory.edu.

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.