title: Systematic analysis of chromatin interactions at disease associated loci links novel candidate genes to inflammatory bowel disease.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Huispostnummer KA.03.019.0, Lundlaan 6, P.O. Box 85090, 3508, AB, Utrecht, The Netherlands.
authors.forename: Claartje A
authors.initials: CA
authors.lastname: Meddens
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Noortje A M
authors.initials: NA
authors.lastname: van den Dungen
authors.affiliation: Vascular Biology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Hassan
authors.initials: H
authors.lastname: Foroughi Asl
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Huispostnummer KA.03.019.0, Lundlaan 6, P.O. Box 85090, 3508, AB, Utrecht, The Netherlands.
authors.forename: Hemme J
authors.initials: HJ
authors.lastname: Hijma
authors.affiliation: Department of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.|Hubrecht Institute, Utrecht, The Netherlands.
authors.forename: Edwin P J G
authors.initials: EP
authors.lastname: Cuppen
authors.affiliation: Vascular Biology Unit, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.|Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
authors.forename: Johan L M
authors.initials: JL
authors.lastname: Björkegren
authors.affiliation: Department of Cardiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.|Durrer Center for Cardiogenetic Research, Utrecht, The Netherlands.|Institute of Cardiovascular Science, University College London, London, UK.
authors.forename: Folkert W
authors.initials: FW
authors.lastname: Asselbergs
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Huispostnummer KA.03.019.0, Lundlaan 6, P.O. Box 85090, 3508, AB, Utrecht, The Netherlands.
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, Huispostnummer KA.03.019.0, Lundlaan 6, P.O. Box 85090, 3508, AB, Utrecht, The Netherlands. m.mokry@umcutrecht.nl.
authors.forename: Michal
authors.initials: M
authors.lastname: Mokry
mesh_terms: D000071183:Autophagy-Related Proteins / Q000235:genetics / Q000378:metabolism; D002843:Chromatin / Q000235:genetics*; D004843:Epistasis, Genetic; D015870:Gene Expression; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics* / Q000378:metabolism; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012045:Regulatory Sequences, Nucleic Acid; D015203:Reproducibility of Results; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; D002843:Chromatin; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D053709:Interleukin-10 Receptor alpha Subunit; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins
keywords: Candidate genes; Chromatin interactions; DNA regulation; Enhancer elements; Epigenetics; Genetics; Genome-wide association studies (GWAS); Inflammatory bowel disease