IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-06-21

AUTHORS

Yukihide Momozawa, Julia Dmitrieva, Emilie Théâtre, Valérie Deffontaine, Souad Rahmouni, Benoît Charloteaux, François Crins, Elisa Docampo, Mahmoud Elansary, Ann-Stephan Gori, Christelle Lecut, Rob Mariman, Myriam Mni, Cécile Oury, Ilya Altukhov, Dmitry Alexeev, Yuri Aulchenko, Leila Amininejad, Gerd Bouma, Frank Hoentjen, Mark Löwenberg, Bas Oldenburg, Marieke J. Pierik, Andrea E. vander Meulen-de Jong, C. Janneke van der Woude, Marijn C. Visschedijk, The International IBD Genetics Consortium, Mark Lathrop, Jean-Pierre Hugot, Rinse K. Weersma, Martine De Vos, Denis Franchimont, Severine Vermeire, Michiaki Kubo, Edouard Louis, Michel Georges

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. More... »

PAGES

2427

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  • Journal

    TITLE

    Nature Communications

    ISSUE

    1

    VOLUME

    9

    Author Affiliations

  • Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, 230-0045, Yokohama, Kanagawa, Japan
  • Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l’Hôpital, 4000, Liège, Belgium
  • Laboratory of Thrombosis and Hemostasis, GIGA-R, University of Liège (B34), 1 Avenue de l’Hôpital, 4000, Liège, Belgium
  • Moscow Institute of Physics and Technology, Institutskiy Pereulok 9, 141700, Dolgoprudny, Russian Federation
  • Novosibirsk State University, Pirogova ave. 2, 630090, Novosibirsk, Russian Federation
  • Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, EH8 9AG, Teviot Place, Edinburgh, UK
  • Gastroentérologie Médicale, Faculté de Médicine, Université Libre de Bruxelles, Route de Lennik 808, 1070, Anderlecht, Belgium
  • Department of Gastroenterology and Hepatology, VU University Medical Centre, 1081 HV, Amsterdam, The Netherlands
  • Department of Gastroenterology and Hepatology, University Medical Centre St. Radboud, 6525 GA, Nijmegen, The Netherlands
  • Department of Gastroenterology and Hepatology, Amsterdam Medical Centre, 1105 AZ, Amsterdam, The Netherlands
  • Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, 3584 cX, Utrecht, The Netherlands
  • Department of Gastroenterology and Hepatology, University Medical Centre Maastricht, 6229 HX, Maastricht, The Netherlands
  • Department of Gastroenterology and Hepatology, Leiden University Medical Centre, 2333 ZA, Leiden, The Netherlands
  • Department of Gastroenterology and Hepatology, Erasmus Medical Centre, 3015 CE, Rotterdam, The Netherlands
  • Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands
  • McGill University Centre for Molecular and Computational Genomics, 740 Dr. Penfield Avenue, H3A 0G1, Montreal, QC, Canada
  • UMR 1149 INSERM/Université Paris-Diderot Sorbonne Paris-Cité, Assistance Publique Hôpitaux de Paris, 48 Bd Sérurier, 75019, Paris, France
  • Department of Gastroenterology, University Hospital, De Pintelaan 185, 9000, Gent, Belgium
  • Translational Research in Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, UZ Herestraat 49, 3000, Leuven, Belgium
  • CHU-Liège and Unit of Gastroenterology, GIGA-R & Faculty of Medicine, University of Liège, 1 Avenue de l’Hôpital, 4000, Liège, Belgium
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-018-04365-8

    DOI

    http://dx.doi.org/10.1038/s41467-018-04365-8

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1104656541

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/29930244


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