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

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, Mark Lathrop, Jean-Pierre Hugot, Rinse K. Weersma, Martine Vos, Denis Franchimont, Severine Vermeire, Michiaki Kubo, Edouard Louis and Michel Georges ()
Additional contact information
Yukihide Momozawa: University of Liège (B34)
Julia Dmitrieva: University of Liège (B34)
Emilie Théâtre: University of Liège (B34)
Valérie Deffontaine: University of Liège (B34)
Souad Rahmouni: University of Liège (B34)
Benoît Charloteaux: University of Liège (B34)
François Crins: University of Liège (B34)
Elisa Docampo: University of Liège (B34)
Mahmoud Elansary: University of Liège (B34)
Ann-Stephan Gori: University of Liège (B34)
Christelle Lecut: University of Liège (B34)
Rob Mariman: University of Liège (B34)
Myriam Mni: University of Liège (B34)
Cécile Oury: University of Liège (B34)
Ilya Altukhov: Moscow Institute of Physics and Technology
Dmitry Alexeev: Novosibirsk State University
Yuri Aulchenko: PolyOmica
Leila Amininejad: Université Libre de Bruxelles
Gerd Bouma: VU University Medical Centre
Frank Hoentjen: University Medical Centre St. Radboud
Mark Löwenberg: Amsterdam Medical Centre
Bas Oldenburg: University Medical Centre Utrecht
Marieke J. Pierik: University Medical Centre Maastricht
Andrea E. vander Meulen- de Jong: Leiden University Medical Centre
C. Janneke van der Woude: Erasmus Medical Centre
Marijn C. Visschedijk: University of Groningen and University Medical Center Groningen
Mark Lathrop: McGill University Centre for Molecular and Computational Genomics
Jean-Pierre Hugot: UMR 1149 INSERM/Université Paris-Diderot Sorbonne Paris-Cité, Assistance Publique Hôpitaux de Paris
Rinse K. Weersma: University of Groningen and University Medical Center Groningen
Martine Vos: University Hospital
Denis Franchimont: Université Libre de Bruxelles
Severine Vermeire: KU Leuven
Michiaki Kubo: RIKEN Center for Integrative Medical Science
Edouard Louis: University of Liège
Michel Georges: University of Liège (B34)

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04365-8

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DOI: 10.1038/s41467-018-04365-8

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