Transcriptome profiling of human ulcerative colitis mucosa reveals altered expression of pathways enriched in genetic susceptibility loci.
Human colonic mucosa altered by inflammation due to ulcerative colitis (UC) displays a drastically altered pattern of gene expression compared with healthy tissue. We aimed to understand the underlying molecular pathways influencing these differences by analyzing three publically-available, independently-generated microarray datasets of gene expression from endoscopic biopsies of the colon. Gene set enrichment analysis (GSEA) revealed that all three datasets share 87 gene sets upregulated in UC lesions and 8 gene sets downregulated (false discovery rate <0.05). The upregulated pathways were dominated by gene sets involved in immune function and signaling, as well as the control of mitosis. We applied pathway analysis to genotype data derived from genome-wide association studies (GWAS) of UC, consisting of 5,584 cases and 11,587 controls assembled from eight European-ancestry cohorts. The upregulated pathways derived from the gene expression data showed a highly significant overlap with pathways derived from the genotype data (33 of 56 gene sets, hypergeometric P = 1.49 × 10(-19)). This study supports the hypothesis that heritable variation in gene expression as measured by GWAS signals can influence key pathways in the development of disease, and that comparison of genetic susceptibility loci with gene expression signatures can differentiate key drivers of inflammation from secondary effects on gene expression of the inflammatory process.
Center for Applied Genomics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Christopher J
CJ
Cardinale
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, United States of America.
Zhi
Z
Wei
Center for Applied Genomics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Jin
J
Li
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, United States of America.
Junfei
J
Zhu
Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, United States of America.
Mengnan
M
Gu
Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Robert N
RN
Baldassano
Center for Applied Genomics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Struan F A
SF
Grant
Center for Applied Genomics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Hakon
H
Hakonarson
D003093:Colitis, Ulcerative / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016099:Endoscopy, Gastrointestinal; D020869:Gene Expression Profiling / Q000379:methods*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D015398:Signal Transduction