Characterization of candidate genes in inflammatory bowel disease-associated risk loci.
GWAS have linked SNPs to risk of inflammatory bowel disease (IBD), but a systematic characterization of disease-associated genes has been lacking. Prior studies utilized microarrays that did not capture many genes encoded within risk loci or defined expression quantitative trait loci (eQTLs) using peripheral blood, which is not the target tissue in IBD. To address these gaps, we sought to characterize the expression of IBD-associated risk genes in disease-relevant tissues and in the setting of active IBD. Terminal ileal (TI) and colonic mucosal tissues were obtained from patients with Crohn's disease or ulcerative colitis and from healthy controls. We developed a NanoString code set to profile 678 genes within IBD risk loci. A subset of patients and controls were genotyped for IBD-associated risk SNPs. Analyses included differential expression and variance analysis, weighted gene coexpression network analysis, and eQTL analysis. We identified 116 genes that discriminate between healthy TI and colon samples and uncovered patterns in variance of gene expression that highlight heterogeneity of disease. We identified 107 coexpressed gene pairs for which transcriptional regulation is either conserved or reversed in an inflammation-independent or -dependent manner. We demonstrate that on average approximately 60% of disease-associated genes are differentially expressed in inflamed tissue. Last, we identified eQTLs with either genotype-only effects on expression or an interaction effect between genotype and inflammation. Our data reinforce tissue specificity of expression in disease-associated candidate genes, highlight genes and gene pairs that are regulated in disease-relevant tissue and inflammation, and provide a foundation to advance the understanding of IBD pathogenesis.
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease.|Center for Computational and Integrative Biology.
Joanna M
JM
Peloquin
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease.|Center for Computational and Integrative Biology.
Gautam
G
Goel
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease.|Center for Computational and Integrative Biology.
Lingjia
L
Kong
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Hailiang
H
Huang
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Talin
T
Haritunians
Department of Medicine, Center for Gastrointestinal Biology and Disease, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
R Balfour
RB
Sartor
Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Mark J
MJ
Daly
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
Rodney D
RD
Newberry
F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Dermot P
DP
McGovern
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease.
Vijay
V
Yajnik
Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Sergio A
SA
Lira
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease.|Center for Computational and Integrative Biology.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
Ramnik J
RJ
Xavier
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