Faculty Collaboration Database

Prioritizing Crohn's disease genes by integrating association signals with gene expression implicates monocyte subsets. Genes Immun 2019 Sep;20(7):577-588

Date

01/30/2019

Pubmed ID

30692607

Pubmed Central ID

PMC7446136

DOI

10.1038/s41435-019-0059-y

Scopus ID

2-s2.0-85060796082 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

Genome-wide association studies have identified ~170 loci associated with Crohn's disease (CD) and defining which genes drive these association signals is a major challenge. The primary aim of this study was to define which CD locus genes are most likely to be disease related. We developed a gene prioritization regression model (GPRM) by integrating complementary mRNA expression datasets, including bulk RNA-Seq from the terminal ileum of 302 newly diagnosed, untreated CD patients and controls, and in stimulated monocytes. Transcriptome-wide association and co-expression network analyses were performed on the ileal RNA-Seq datasets, identifying 40 genome-wide significant genes. Co-expression network analysis identified a single gene module, which was substantially enriched for CD locus genes and most highly expressed in monocytes. By including expression-based and epigenetic information, we refined likely CD genes to 2.5 prioritized genes per locus from an average of 7.8 total genes. We validated our model structure using cross-validation and our prioritization results by protein-association network analyses, which demonstrated significantly higher CD gene interactions for prioritized compared with non-prioritized genes. Although individual datasets cannot convey all of the information relevant to a disease, combining data from multiple relevant expression-based datasets improves prediction of disease genes and helps to further understanding of disease pathogenesis.

Author List

Gettler K, Giri M, Kenigsberg E, Martin J, Chuang LS, Hsu NY, Denson LA, Hyams JS, Griffiths A, Noe JD, Crandall WV, Mack DR, Kellermayer R, Abraham C, Hoffman G, Kugathasan S, Cho JH

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
Algorithms
Case-Control Studies
Child
Child, Preschool
Crohn Disease
Female
Gene Regulatory Networks
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Monocytes
Polymorphism, Single Nucleotide
Quantitative Trait Loci
Sequence Analysis, DNA
Software
Transcriptome