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; Steven R. Brant; International IBD Genetics Consortium

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)

06/21/2018

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: Yukihide Momozawa - Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
Julia Dmitrieva - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Emilie Théâtre - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Valérie Deffontaine - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Souad Rahmouni - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Benoît Charloteaux - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
François Crins - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Elisa Docampo - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Mahmoud Elansary - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Ann-Stephan Gori - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Christelle Lecut - Laboratory of Thrombosis and Hemostasis, GIGA-R, University of Liège (B34), 1 Avenue de l'Hôpital, 4000, Liège, Belgium
Rob Mariman - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Myriam Mni - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Cécile Oury - Laboratory of Thrombosis and Hemostasis, GIGA-R, University of Liège (B34), 1 Avenue de l'Hôpital, 4000, Liège, Belgium
Ilya Altukhov - Moscow Institute of Physics and Technology, Institutskiy Pereulok 9, Dolgoprudny, 141700, Russian Federation
Dmitry Alexeev - Novosibirsk State University, Pirogova ave. 2, Novosibirsk, 630090, Russian Federation
Yuri Aulchenko - Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK
Leila Amininejad - Gastroentérologie Médicale, Faculté de Médicine, Université Libre de Bruxelles, Route de Lennik 808, Anderlecht, 1070, Belgium
Gerd Bouma - Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, 1081 HV, The Netherlands
Frank Hoentjen - Department of Gastroenterology and Hepatology, University Medical Centre St. Radboud, Nijmegen, 6525 GA, The Netherlands
Mark Löwenberg - Department of Gastroenterology and Hepatology, Amsterdam Medical Centre, Amsterdam, 1105 AZ, The Netherlands
Bas Oldenburg - Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, 3584 cX, Utrecht, The Netherlands
Marieke J Pierik - Department of Gastroenterology and Hepatology, University Medical Centre Maastricht, Maastricht, 6229 HX, The Netherlands
Andrea E Vander Meulen-de Jong - Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, 2333 ZA, The Netherlands
C Janneke van der Woude - Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, 3015 CE, The Netherlands
Marijn C Visschedijk - Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands
Mark Lathrop - McGill University Centre for Molecular and Computational Genomics, 740 Dr. Penfield Avenue, Montreal, H3A 0G1, QC, Canada
Jean-Pierre Hugot - UMR 1149 INSERM/Université Paris-Diderot Sorbonne Paris-Cité, Assistance Publique Hôpitaux de Paris, 48 Bd Sérurier, Paris, 75019, France
Rinse K Weersma - Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands
Martine De Vos - Department of Gastroenterology, University Hospital, De Pintelaan 185, Gent, 9000, Belgium
Denis Franchimont - Gastroentérologie Médicale, Faculté de Médicine, Université Libre de Bruxelles, Route de Lennik 808, Anderlecht, 1070, Belgium
Severine Vermeire - Translational Research in Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, UZ Herestraat 49, Leuven, 3000, Belgium
Michiaki Kubo - Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
Edouard Louis - CHU-Liège and Unit of Gastroenterology, GIGA-R & Faculty of Medicine, University of Liège, 1 Avenue de l'Hôpital, Liège, 4000, Belgium
Michel Georges - Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium. michel.georges@ulg.ac.be
Steven R. Brant - Rutgers University, Medicine - Gastroenterology and Hepatology (RWJMS)
International IBD Genetics Consortium
Publication Details: Nature communications, Vol.9(1)
Date published: 06/21/2018
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
Academic Unit: Medicine - Gastroenterology and Hepatology (RWJMS)
Language: English
Resource Type: Journal article
Identifiers: 991031664407204646