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

[en] 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 dataset (9 disease-relevant cell types) and identify 23,650 cis-eQTL. We show that these are determined by ∼9,720 regulatory modules, of which ∼3,000 operate in multiple tissues and ∼970 on multiple genes. We identify regulatory modules that are driveing the disease association for 63 of the 200 risk loci, and show that these are enriched in multigenic modules. We resequence 45 of the corresponding 100 candidate genes in 6,600 Crohn disease (CD) cases and 5,500 controls and show that they are significantly enriched in causative genes. Our analyses indicate that ≥10-fold larger sample sizes will be required to demonstrate the causality of individual genes using standard burden tests.

Disciplines :

Gastroenterology & hepatology

Author, co-author :

Momozawa, Yukihide

Dmitrieva, Joelia Borisovna ; Université de Liège - ULiège > Dpt. de gestion vétérinaire des Ressources Animales (DRA) > GIGA-R : Génomique animale

Theatre, Emilie ; Université de Liège > Génomique animale > GIGA-R : Génomique animale

Deffontaine, Valérie

Rahmouni, Souad ; Université de Liège - ULiège > Département des sciences cliniques > GIGA-R:Immunopath. - Maladies infect. et médec. inter. gén.

Charloteaux, Benoît ; Université de Liège - ULiège > GIGA-Research

Crins, François

Elansary, Mahmoud ; Université de Liège - ULiège > Dpt. de gestion vétérinaire des Ressources Animales (DRA) > GIGA-R : Génomique animale

Gori, Ann-Stephan ; Université de Liège - ULiège > GIGA-Research

LECUT, Christelle ; Centre Hospitalier Universitaire de Liège - CHU > Service d'hématologie biologique et immuno-hématologie

More authors (20 more)

Language :

English

Title :

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

Publication date :

2018

Journal title :

Nature Communications

eISSN :

2041-1723

Publisher :

Nature Publishing Group, United Kingdom

Peer reviewed :

Peer Reviewed verified by ORBi

European Projects :

H2020 - 733100 - SYSCID - A Systems medicine approach to chronic inflammatory disease

Funders :

CE - Commission Européenne
Union Européenne

Available on ORBi :

since 04 June 2018

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