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IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
Unit of Animal Genomics, WELBIO, GIGA-R, Faculty of Veterinary Medicine, University of Liège (B34), Liège, Belgium; Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, Japan.
Örebro University, School of Medical Sciences. Department of Gastroenterology.ORCID iD: 0000-0003-0122-7234
Department of Biostatistics, School of Public Health, Yale University, New Haven CT, United States.
Number of Authors: 1952018 (English)In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 9, article id 2427Article in journal (Refereed) Published
Abstract [en]

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 similar to 9720 regulatory modules, of which similar to 3000 operate in multiple tissues and similar to 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.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018. Vol. 9, article id 2427
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:oru:diva-68044DOI: 10.1038/s41467-018-04365-8ISI: 000435794500006PubMedID: 29930244Scopus ID: 2-s2.0-85048925642OAI: oai:DiVA.org:oru-68044DiVA, id: diva2:1235285
Note

Funding Agencies:

WELBIO (CAUSIBD)  

BELSPO (BeMGI)  

Horizon 2020 (SYSCID)  

Fonds de la Recherche Scientifique de Belgique (F.R.S.-FNRS)  2.5020.11 

Japan Agency for Medical Research and Development  

Ministry of Education, Culture, Sports, Sciences and Technology of the Japanese government  

Russian Ministry of Science and Education under 5-100 Excellence Programme  

VIDI grant from the Netherlands Organisation for Scientific Research (NWO)  016.136.308 

Netherlands Federation of University Medical Centres  

Dutch Government

Available from: 2018-07-25 Created: 2018-07-25 Last updated: 2018-07-25Bibliographically approved

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Halfvarson, Jonas

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