TY - JOUR
T1 - IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
AU - The International IBD Genetics Consortium
AU - Momozawa, Yukihide
AU - Dmitrieva, Julia
AU - Théâtre, Emilie
AU - Deffontaine, Valérie
AU - Rahmouni, Souad
AU - Charloteaux, Benoît
AU - Crins, François
AU - Docampo, Elisa
AU - Elansary, Mahmoud
AU - Gori, Ann Stephan
AU - Lecut, Christelle
AU - Mariman, Rob
AU - Mni, Myriam
AU - Oury, Cécile
AU - Altukhov, Ilya
AU - Alexeev, Dmitry
AU - Aulchenko, Yuri
AU - Amininejad, Leila
AU - Bouma, Gerd
AU - Hoentjen, Frank
AU - Löwenberg, Mark
AU - Oldenburg, Bas
AU - Pierik, Marieke J.
AU - Vander Meulen-De Jong, Andrea E.
AU - Van Der Woude, C. Janneke
AU - Visschedijk, Marijn C.
AU - Lathrop, Mark
AU - Hugot, Jean Pierre
AU - Weersma, Rinse K.
AU - De Vos, Martine
AU - Franchimont, Denis
AU - Vermeire, Severine
AU - Kubo, Michiaki
AU - Louis, Edouard
AU - Georges, Michel
AU - Abraham, Clara
AU - Achkar, Jean Paul
AU - Ahmad, Tariq
AU - Ananthakrishnan, Ashwin N.
AU - Andersen, Vibeke
AU - Anderson, Carl A.
AU - Andrews, Jane M.
AU - Annese, Vito
AU - Aumais, Guy
AU - Baidoo, Leonard
AU - Baldassano, Robert N.
AU - Bampton, Peter A.
AU - Barclay, Murray
AU - Barrett, Jeffrey C.
AU - Winkelmann, Juliane
N1 - Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85048925642
U2 - 10.1038/s41467-018-04365-8
DO - 10.1038/s41467-018-04365-8
M3 - Article
C2 - 29930244
AN - SCOPUS:85048925642
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 2427
ER -