A functional genomics predictive network model identifies regulators of inflammatory bowel disease

Peters, Lauren; Perrigoue, Jacqueline; Mortha, Arthur; Iuga, Alina; Song, Won‐Min; Neiman, Eric M.; Llewellyn, Sean R.; Narzo, Antonio Di; Kidd, Brian; Telesco, Shannon; Zhao, Yang; Stojmirović, Aleksandar; Sendecki, Jocelyn; Shameer, Khader; Miotto, Riccardo; Losic, Bojan; Shah, Hardik; Lee, Eunjee; Wang, Minghui; Faith, Jeremiah J.; Kasarskis, Andrew; Brodmerkel, Carrie; Curran, Mark; Das, Anuk; Friedman, Joshua R.; Fukui, Yoshihiro; Humphrey, Mary Beth; Iritani, Brian M.; Sibinga, Nicholas E.S.; Tarrant, Teresa K.; Argmann, Carmen; Hao, Ke; Roussos, Panos; Zhu, Jun; Zhang, Bin; Dobrin, Radu; Mayer, Lloyd; Schadt, Eric E.

doi:10.1038/ng.3947

Cited by 223 publications

(234 citation statements)

References 78 publications

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“…The discovery of NOD2 as the first, and most important, susceptibility gene1 2 was then followed by identification of over 200 other loci,3 4 but these genetic contributions together likely only explain 19%–26% of the hereditary variance of IBD 5. Genetic studies have identified defects in innate immunity in Crohn disease (CD) and altered barrier function in Ulcerative Colitis (UC) as some of the key players in disease susceptibility 6 7…”

Section: Introductionmentioning

confidence: 99%

Evolving role of diet in the pathogenesis and treatment of inflammatory bowel diseases

Levine

Boneh

Wine

2018

Gut

293

284

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Recent advances in basic and clinical science over the last 3 years have dramatically altered our appreciation of the role of diet in inflammatory bowel diseases (IBD). The marked increase in incidence of these diseases along with the important role of non-genetic susceptibility among patients with IBD has highlighted that these diseases have a strong environmental component. Progress in the field of microbiome and IBD has demonstrated that microbiome appears to play an important role in pathogenesis, and that diet may in turn impact the composition and functionality of the microbiome. Uncontrolled clinical studies have demonstrated that various dietary therapies such as exclusive enteral nutrition and newly developed exclusion diets might be potent tools for induction of remission at disease onset, for patients failing biologic therapy, as a treatment for disease complications and in reducing the need for surgery. We review these advances from bench to bedside, along with the need for better clinical trials to support these interventions.

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Section: Introductionmentioning

confidence: 99%

Evolving role of diet in the pathogenesis and treatment of inflammatory bowel diseases

Levine

Boneh

Wine

2018

Gut

293

284

View full text Add to dashboard Cite

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“…Detailed descriptions of these data sets are available in the published studies. 11,18,19 2.3 | Transcriptome-wide association study The FUSION software was applied to the GWAS summary data of IBD for tissue-related TWAS analysis. Briefly, FUSION computed the gene expression weights of various tissues using a small set of individuals with both genotype and gene expression data.…”

Section: Mrna Expression Profiles Of Ibdmentioning

confidence: 99%

Integrative analysis of transcriptome‐wide association study data and messenger RNA expression profiles identified candidate genes and pathways for inflammatory bowel disease

Cheng

Liang

Wen

et al. 2019

J of Cellular Biochemistry

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Inflammatory bowel disease (IBD) is a complex disease, resulting from abnormal immune response to intestinal tract microbiota in genetically susceptible individuals. Crohn's disease and ulcerative colitis (UC) are the two major types of IBD. Transcriptome‐wide association study (TWAS) of IBD was first performed using a large‐scale genome‐wide association study summary data sets of IBD. The FUSION software was applied for TWAS, considering various tissues and cells. The genes identified by TWAS were then validated by the gene expression profiling data sets of IBD. The functional annotation and potential pathways of common differentially expressed genes were further subjected to gene ontology (GO) and pathway enrichment analysis. Integrative analysis of TWAS and messenger RNA (mRNA) expression data detected several tissues related common genes for UC, such as HLA‐DRB1 (PTWAS = 0.024; mRNA expression ratio = 1.700) and TAP2 in colon (P TWAS = 0.047; mRNA expression ratio = 2.170). Further comparing the GO enrichment analysis results of TWAS and mRNA expression data, we identified 11 common GO terms for UC, such as plasma membrane (P value = 5.08 × 10−10) in intestinal tissues and immune response (P = 0.001) in peripheral blood. We also detected several common pathways for UC, including cell adhesion molecules (P = 0.003) in intestinal tissues, IBD (P = 0.049) in whole blood and phagosome (P = 0.0003) in peripheral blood. Our study results provide novel clues for understanding the genetic mechanism of IBD.

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“…Recently, Peters et al used individual networks constructed from molecular data generated from intestinal samples isolated from three populations of patients with IBD at different stages of disease, including two adult and pediatric cohorts of IBD. As a result, they developed a predictive model of the immune component of IBD that informs causal relationships among loci previously linked to IBD through GWAS using functional and regulatory annotations that relate to the cells, tissues, and pathophysiology of IBD.…”

Section: Beyond Genetics: Ibdomics—systems Biology and Integrative Mementioning

confidence: 99%

“…This network revealed potential key drivers of IBD pathogenesis. Among the key drivers were numerous known VEO‐IBD genes, but also inborn errors of immunity and new candidates that were showed to have a role in inflammatory immune response …”

Section: Beyond Genetics: Ibdomics—systems Biology and Integrative Mementioning

confidence: 99%

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

Pázmándi

Kalinichenko

Ardy

et al. 2018

Immunological Reviews

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Summary Rare, monogenetic diseases present unique models to dissect gene functions and biological pathways, concomitantly enhancing our understanding of the etiology of complex (and often more common) traits. Although inflammatory bowel disease (IBD) is a generally prototypic complex disease, it can also manifest in an early‐onset, monogenic fashion, often following Mendelian modes of inheritance. Recent advances in genomic technologies have spurred the identification of genetic defects underlying rare, very early‐onset IBD (VEO‐IBD) as a disease subgroup driven by strong genetic influence, pinpointing key players in the delicate homeostasis of the immune system in the gut and illustrating the intimate relationships between bowel inflammation, systemic immune dysregulation, and primary immunodeficiency with increased susceptibility to infections. As for other human diseases, it is likely that adult‐onset diseases may represent complex diseases integrating the effects of host genetic susceptibility and environmental triggers. Comparison of adult‐onset IBD and VEO‐IBD thus provides beautiful models to investigate the relationship between monogenic and multifactorial/polygenic diseases. This review discusses the present and novel findings regarding monogenic IBD as well as key questions and future directions of IBD research.

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A functional genomics predictive network model identifies regulators of inflammatory bowel disease

Cited by 223 publications

References 78 publications

Evolving role of diet in the pathogenesis and treatment of inflammatory bowel diseases

Evolving role of diet in the pathogenesis and treatment of inflammatory bowel diseases

Integrative analysis of transcriptome‐wide association study data and messenger RNA expression profiles identified candidate genes and pathways for inflammatory bowel disease

Early‐onset inflammatory bowel disease as a model disease to identify key regulators of immune homeostasis mechanisms

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