Meddens, CA;
Harakalova, M;
van den Dungen, NAM;
Asl, HF;
Hijma, HJ;
Cuppen, EPJG;
Bjorkegren, JLM;
... Mokry, M; + view all
(2016)
Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease.
Genome Biology
, 17
, Article 247. 10.1186/s13059-016-1100-3.
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Abstract
BACKGROUND: Genome-wide association studies (GWAS) have revealed many susceptibility loci for complex genetic diseases. For most loci, the causal genes have not been identified. Currently, the identification of candidate genes is predominantly based on genes that localize close to or within identified loci. We have recently shown that 92 of the 163 inflammatory bowel disease (IBD)-loci co-localize with non-coding DNA regulatory elements (DREs). Mutations in DREs can contribute to IBD pathogenesis through dysregulation of gene expression. Consequently, genes that are regulated by these 92 DREs are to be considered as candidate genes. This study uses circular chromosome conformation capture-sequencing (4C-seq) to systematically analyze chromatin-interactions at IBD susceptibility loci that localize to regulatory DNA. RESULTS: Using 4C-seq, we identify genomic regions that physically interact with the 92 DRE that were found at IBD susceptibility loci. Since the activity of regulatory elements is cell-type specific, 4C-seq was performed in monocytes, lymphocytes, and intestinal epithelial cells. Altogether, we identified 902 novel IBD candidate genes. These include genes specific for IBD-subtypes and many noteworthy genes including ATG9A and IL10RA. We show that expression of many novel candidate genes is genotype-dependent and that these genes are upregulated during intestinal inflammation in IBD. Furthermore, we identify HNF4α as a potential key upstream regulator of IBD candidate genes. CONCLUSIONS: We reveal many novel and relevant IBD candidate genes, pathways, and regulators. Our approach complements classical candidate gene identification, links novel genes to IBD and can be applied to any existing GWAS data.
| Type: | Article |
|---|---|
| Title: | Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13059-016-1100-3 |
| Publisher version: | http://doi.org/10.1186/s13059-016-1100-3 |
| Language: | English |
| Additional information: | © The Author(s). 2016. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Biotechnology & Applied Microbiology, Genetics & Heredity, Inflammatory bowel disease, Genetics, Epigenetics, Genome-wide association studies (GWAS), Enhancer elements, Chromatin interactions, DNA regulation, Candidate genes, GENOME-WIDE ASSOCIATION, CAPTURE HI-C, RISK LOCI, SUSCEPTIBILITY LOCI, CROHN-DISEASE, HISTONE MODIFICATIONS, ULCERATIVE-COLITIS, HIGH-RESOLUTION, HUMAN-CELLS, EXPRESSION |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Health Informatics |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1570525 |
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