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Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort.
Genes Immun. 2019 02; 20(2):131-142.GI

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.

Authors+Show Affiliations

Department of Human Genetics, Emory University, Atlanta, GA, USA.Department of Human Genetics, Emory University, Atlanta, GA, USA.Department of Pediatrics, Emory University, Atlanta, GA, USA.Department of Pediatrics, Emory University, Atlanta, GA, USA.Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Broad Institute of MIT and Harvard, Cambridge, MA, USA.Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.Department of Pediatrics, University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA, USA.Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Medical College of Wisconsin, Milwaukee, WI, USA.Division of Digestive Diseases, Hepatology, and Nutrition, Connecticut Children's Medical Center, Hartford, CT, USA.Department of Pediatric Gastroenterology, Nationwide Children's Hospital, The Ohio State University College of Medicine, Columbus, OH, USA.Department of Pediatrics, The University of Chicago Comer Children's Hospital, Chicago, IL, USA.Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA.Department of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA.Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.Department of Pediatrics, Mount Sinai Hospital, New York, NY, USA.Department of Pediatrics, Hasbro Children's Hospital, Providence, RI, USA.Department of Pediatrics, Dalhousie University, Halifax, NS, Canada.Broad Institute of MIT and Harvard, Cambridge, MA, USA.Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.Department of Pediatrics, Emory University, Atlanta, GA, USA.Department of Human Genetics, Emory University, Atlanta, GA, USA. mzwick@emory.edu.

Pub Type(s)

Journal Article
Research Support, American Recovery and Reinvestment Act
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29593342

Citation

Shaw, Kelly A., et al. "Genetic Variants and Pathways Implicated in a Pediatric Inflammatory Bowel Disease Cohort." Genes and Immunity, vol. 20, no. 2, 2019, pp. 131-142.
Shaw KA, Cutler DJ, Okou D, et al. Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort. Genes Immun. 2019;20(2):131-142.
Shaw, K. A., Cutler, D. J., Okou, D., Dodd, A., Aronow, B. J., Haberman, Y., Stevens, C., Walters, T. D., Griffiths, A., Baldassano, R. N., Noe, J. D., Hyams, J. S., Crandall, W. V., Kirschner, B. S., Heyman, M. B., Snapper, S., Guthery, S., Dubinsky, M. C., Shapiro, J. M., ... Zwick, M. E. (2019). Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort. Genes and Immunity, 20(2), 131-142. https://doi.org/10.1038/s41435-018-0015-2
Shaw KA, et al. Genetic Variants and Pathways Implicated in a Pediatric Inflammatory Bowel Disease Cohort. Genes Immun. 2019;20(2):131-142. PubMed PMID: 29593342.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Genetic variants and pathways implicated in a pediatric inflammatory bowel disease cohort. AU - Shaw,Kelly A, AU - Cutler,David J, AU - Okou,David, AU - Dodd,Anne, AU - Aronow,Bruce J, AU - Haberman,Yael, AU - Stevens,Christine, AU - Walters,Thomas D, AU - Griffiths,Anne, AU - Baldassano,Robert N, AU - Noe,Joshua D, AU - Hyams,Jeffrey S, AU - Crandall,Wallace V, AU - Kirschner,Barbara S, AU - Heyman,Melvin B, AU - Snapper,Scott, AU - Guthery,Stephen, AU - Dubinsky,Marla C, AU - Shapiro,Jason M, AU - Otley,Anthony R, AU - Daly,Mark, AU - Denson,Lee A, AU - Kugathasan,Subra, AU - Zwick,Michael E, Y1 - 2018/03/28/ PY - 2017/06/08/received PY - 2017/09/11/accepted PY - 2017/08/28/revised PY - 2018/3/30/pubmed PY - 2019/4/2/medline PY - 2018/3/30/entrez SP - 131 EP - 142 JF - Genes and immunity JO - Genes Immun VL - 20 IS - 2 N2 - 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. SN - 1476-5470 UR - https://www.unboundmedicine.com/medline/citation/29593342/full_citation L2 - https://doi.org/10.1038/s41435-018-0015-2 DB - PRIME DP - Unbound Medicine ER -