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 De Vos; Denis Franchimont; Severine Vermeire; Michiaki Kubo; Edouard Louis; Michel Georges; International IBD Genetics Consortium; Tariq Ahamed Ahanger

doi:10.1038/s41467-018-04365-8

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

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.9(1), pp.2427-18

2018

DOI: https://doi.org/10.1038/s41467-018-04365-8

PMCID: PMC6013502

PMID: 29930244

Abstract

Adult

Aged

Aged, 80 and over

Cohort Studies

Crohn Disease - genetics

Female

Gene Expression Profiling

Genetic Association Studies

Genetic Predisposition to Disease

Genotype

Humans

Inflammatory Bowel Diseases - genetics

Male

Middle Aged

Multifactorial Inheritance

Polymorphism, Single Nucleotide

Quantitative Trait Loci

Sequence Analysis, DNA

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.

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Title: IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
Creators - without role: Yukihide Momozawa - Walloon Excellence in Lifesciences and Biotechnology
Julia Dmitrieva - Walloon Excellence in Lifesciences and Biotechnology
Emilie Théâtre - University of Liège
Valérie Deffontaine - Walloon Excellence in Lifesciences and Biotechnology
Souad Rahmouni - University of Liège
Benoît Charloteaux - Walloon Excellence in Lifesciences and Biotechnology
François Crins - Walloon Excellence in Lifesciences and Biotechnology
Elisa Docampo - Walloon Excellence in Lifesciences and Biotechnology
Mahmoud Elansary - Walloon Excellence in Lifesciences and Biotechnology
Ann-Stephan Gori - Walloon Excellence in Lifesciences and Biotechnology
Christelle Lecut - University of Liège
Rob Mariman - Walloon Excellence in Lifesciences and Biotechnology
Myriam Mni - University of Liège
Cécile Oury - University of Liège
Ilya Altukhov - Moscow Institute of Physics and Technology (Russia, Dolgoprudnyy) - MIPT
Dmitry Alexeev - Novosibirsk State University
Yuri Aulchenko - University of Edinburgh
Leila Amininejad - Université Libre de Bruxelles
Gerd Bouma - Amsterdam UMC Location VUmc
Frank Hoentjen - Radboud University Medical Center
Mark Löwenberg - Academic Medical Center
Bas Oldenburg - University Medical Center Utrecht
Marieke J Pierik - Department of Gastroenterology and Hepatology, University Medical Centre Maastricht, Maastricht, 6229 HX, The Netherlands
Andrea E Vander Meulen-de Jong - Leiden University
C Janneke van der Woude - Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, 3015 CE, The Netherlands
Marijn C Visschedijk - University of Groningen
Mark Lathrop - McGill University
Jean-Pierre Hugot - Délégation Paris 7
Rinse K Weersma - University of Groningen
Martine De Vos - Ghent University Hospital
Denis Franchimont - Université Libre de Bruxelles
Severine Vermeire - KU Leuven
Michiaki Kubo - RIKEN Center for Integrative Medical Sciences
Edouard Louis - University of Liège
Michel Georges - University of Liège
International IBD Genetics Consortium
Tariq Ahamed Ahanger - Prince Sattam Bin Abdulaziz University
Publication Details: Nature communications, Vol.9(1), pp.2427-18
Grant note: R01 CA141743 / NCI NIH HHS U01 DK062431 / NIDDK NIH HHS P30 DK078392 / NIDDK NIH HHS U01 DK062423 / NIDDK NIH HHS P30 DK043351 / NIDDK NIH HHS U01 DK062420 / NIDDK NIH HHS K08 DK110415 / NIDDK NIH HHS
Identifiers: 9926262908331
Academic Unit: Prince Sattam Bin Abdulaziz University
Language: English
Resource Type: Journal article