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

Publication

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

Journal Paper/Review - Jun 21, 2018

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

PubMed

29930244

Doi

10.1038/s41467-018-04365-8

Citation

Momozawa Y, Hoentjen F, Löwenberg M, Oldenburg B, Pierik M, Vander Meulen-de Jong A, Janneke van der Woude C, Visschedijk M, International IBD Genetics Consortium, Lathrop M, Hugot J, Weersma R, De Vos M, Franchimont D, Vermeire S, Kubo M, Louis E, Bouma G, Amininejad L, Dmitrieva J, Theatre E, Deffontaine V, Rahmouni S, Charloteaux B, Crins F, Docampo E, Elansary M, Gori A, Lecut C, Mariman R, Mni M, Oury C, Altukhov I, Alexeev D, Aulchenko Y, Georges M. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat Commun 2018; 9:2427.

Type

Journal Paper/Review (English)

Journal

Nat Commun 2018; 9

Publication Date

Jun 21, 2018

Issn Electronic

2041-1723

Pages

2427

Brief description/objective

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.