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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

ABSTRACT: GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ?9720 regulatory modules, of which ?3000 operate in multiple tissues and ?970 on multiple genes. We identify regulatory modules that drive the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. Based on these analyses, we resequence 45 of the corresponding 100 candidate genes in 6600 Crohn disease (CD) cases and 5500 controls, and show with burden tests that they include likely causative genes. Our analyses indicate that ?10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.

SUBMITTER: Momozawa Y

PROVIDER: S-EPMC6013502 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

Momozawa Yukihide Y Dmitrieva Julia J Théâtre Emilie E Deffontaine Valérie V Rahmouni Souad S Charloteaux Benoît B Crins François F Docampo Elisa E Elansary Mahmoud M Gori Ann-Stephan AS Lecut Christelle C Mariman Rob R Mni Myriam M Oury Cécile C Altukhov Ilya I Alexeev Dmitry D Aulchenko Yuri Y Amininejad Leila L Bouma Gerd G Hoentjen Frank F Löwenberg Mark M Oldenburg Bas B Pierik Marieke J MJ Vander Meulen-de Jong Andrea E AE Janneke van der Woude C C Visschedijk Marijn C MC Lathrop Mark M Hugot Jean-Pierre JP Weersma Rinse K RK De Vos Martine M Franchimont Denis D Vermeire Severine S Kubo Michiaki M Louis Edouard E Georges Michel M

Nature communications 20180621 1

GWAS have identified >200 risk loci for Inflammatory Bowel Disease (IBD). The majority of disease associations are known to be driven by regulatory variants. To identify the putative causative genes that are perturbed by these variants, we generate a large transcriptome data set (nine disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9720 regulatory modules, of which ∼3000 operate in multiple tissues and ∼970 on multiple genes. We identify regulator ...[more]

PMID: 29930244

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Project description:BackgroundEchinococcosis caused by larval of Echinococcus is prevalent all over the world. Although clinical experience showed that the presence of tapeworms could not be found in liver lesions, the repeated infection and aggravation of lesions still occur in the host. Here, this study constructed a multifactor-driven disease-related dysfunction network to explore the potential molecular pathogenesis mechanism in different hosts after E.multilocularis infection.MethodFirst, iTRAQ sequencing was performed on human liver infected with E.multilocularis. Second, obtained microRNAs(miRNAs) expression profiles of humans and canine infected with Echinococcus from the GEO database. In addition, we also performed differential expression analysis, protein interaction network analysis, enrichment analysis, and crosstalk analysis to obtain genes and modules related to E.multilocularis infection. Pivot analysis is used to calculate the potential regulatory effects of multiple factors on the module and identify related non-coding RNAs(ncRNAs) and transcription factors(TFs). Finally, we screened the target genes of miRNAs of Echinococcus to further explore its infection mechanism.ResultsA total of 267 differentially expressed proteins from humans and 3,635 differentially expressed genes from canine were obtained. They participated in 16 human-related dysfunction modules and five canine-related dysfunction modules, respectively. Both human and canine dysfunction modules are significantly involved in BMP signaling pathway and TGF-beta signaling pathway. In addition, pivot analysis found that 1,129 ncRNAs and 110 TFs significantly regulated human dysfunction modules, 158 ncRNAs and nine TFs significantly regulated canine dysfunction modules. Surprisingly, the Echinococcus miR-184 plays a role in the pathogenicity regulation by targeting nine TFs and one ncRNA in humans. Similarly, miR-184 can also cause physiological dysfunction by regulating two transcription factors in canine.ConclusionThe results show that the miRNA-184 of Echinococcus can regulate the pathogenic process through various biological functions and pathways. The results laid a solid theoretical foundation for biologists to further explore the pathogenic mechanism of Echinococcosis.

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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

Publications

IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes.

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