TY - JOUR
T1 - IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
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 - The International IBD Genetics Consortium
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 - Bayless, Theodore M.
AU - Bethge, Johannes
AU - Bitton, Alain
AU - Boucher, Gabrielle
AU - Brand, Stephan
AU - Brandt, Berenice
AU - Brant, Steven R.
AU - Büning, Carsten
AU - Chew, Angela
AU - Cho, Judy H.
AU - Cleynen, Isabelle
AU - Cohain, Ariella
AU - Croft, Anthony
AU - Daly, Mark J.
AU - D'Inca, Renata
AU - Danese, Silvio
AU - De Jong, Dirk
AU - Denapiene, Goda
AU - Denson, Lee A.
AU - Devaney, Kathy L.
AU - Dewit, Olivier
AU - D'Inca, Renata
AU - Dubinsky, Marla
AU - Duerr, Richard H.
AU - Edwards, Cathryn
AU - Ellinghaus, David
AU - Essers, Jonah
AU - Ferguson, Lynnette R.
AU - Festen, Eleonora A.
AU - Fleshner, Philip
AU - Florin, Tim
AU - Franke, Andre
AU - Fransen, Karin
AU - Gearry, Richard
AU - Gieger, Christian
AU - Glas, Jürgen
AU - Goyette, Philippe
AU - Green, Todd
AU - Griffiths, Anne M.
AU - Guthery, Stephen L.
AU - Hakonarson, Hakon
AU - Halfvarson, Jonas
AU - Hanigan, Katherine
AU - Haritunians, Talin
AU - Hart, Ailsa
AU - Hawkey, Chris
AU - Hayward, Nicholas K.
AU - Hedl, Matija
AU - Henderson, Paul
AU - Hu, Xinli
AU - Huang, Hailiang
AU - Hui, Ken Y.
AU - Imielinski, Marcin
AU - Ippoliti, Andrew
AU - Jonaitis, Laimas
AU - Jostins, Luke
AU - Karlsen, Tom H.
AU - Kennedy, Nicholas A.
AU - Khan, Mohammed Azam
AU - Kiudelis, Gediminas
AU - Krishnaprasad, Krupa
AU - Kugathasan, Subra
AU - Kupcinskas, Limas
AU - Latiano, Anna
AU - Laukens, Debby
AU - Lawrance, Ian C.
AU - Lee, James C.
AU - Lees, Charlie W.
AU - Leja, Marcis
AU - Van Limbergen, Johan
AU - Lionetti, Paolo
AU - Liu, Jimmy Z.
AU - Mahy, Gillian
AU - Mansfield, John
AU - Massey, Dunecan
AU - Mathew, Christopher G.
AU - McGovern, Dermot P.B.
AU - Milgrom, Raquel
AU - Mitrovic, Mitja
AU - Montgomery, Grant W.
AU - Mowat, Craig
AU - Newman, William
AU - Ng, Aylwin
AU - Ng, Siew C.
AU - Ng, Sok Meng Evelyn
AU - Nikolaus, Susanna
AU - Ning, Kaida
AU - Nöthen, Markus
AU - Oikonomou, Ioannis
AU - Palmieri, Orazio
AU - Parkes, Miles
AU - Phillips, Anne
AU - Ponsioen, Cyriel Y.
AU - Potocnik, Uros
AU - Prescott, Natalie J.
AU - Proctor, Deborah D.
AU - Radford-Smith, Graham
AU - Rahier, Jean Francois
AU - Raychaudhuri, Soumya
AU - Regueiro, Miguel
AU - Rieder, Florian
AU - Rioux, John D.
AU - Ripke, Stephan
AU - Roberts, Rebecca
AU - Russell, Richard K.
AU - Sanderson, Jeremy D.
AU - Sans, Miquel
AU - Satsangi, Jack
AU - Schadt, Eric E.
AU - Schreiber, Stefan
AU - Schulte, Dominik
AU - Schumm, L. Philip
AU - Scott, Regan
AU - Seielstad, Mark
AU - Sharma, Yashoda
AU - Silverberg, Mark S.
AU - Simms, Lisa A.
AU - Skieceviciene, Jurgita
AU - Spain, Sarah L.
AU - Steinhart, A. Hillary
AU - Stempak, Joanne M.
AU - Stronati, Laura
AU - Sventoraityte, Jurgita
AU - Targan, Stephan R.
AU - Taylor, Kirstin M.
AU - Ter Velde, Anje
AU - Torkvist, Leif
AU - Tremelling, Mark
AU - Van Sommeren, Suzanne
AU - Vasiliauskas, Eric
AU - Verspaget, Hein W.
AU - Walters, Thomas
AU - Wang, Kai
AU - Wang, Ming Hsi
AU - Wei, Zhi
AU - Whiteman, David
AU - Wijmenga, Cisca
AU - Wilson, David C.
AU - Winkelmann, Juliane
AU - Xavier, Ramnik J.
AU - Zhang, Bin
AU - Zhang, Clarence K.
AU - Zhang, Hu
AU - Zhang, Wei
AU - Zhao, Hongyu
AU - Zhao, Zhen Z.
N1 - Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing,adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visithttp://creativecommons.org/licenses/by/4.0/
PY - 2018/6/1
Y1 - 2018/6/1
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.
KW - Genetics research
KW - Genome-wide association studies
KW - Immunogenetics
KW - Inflammatory bowel diseaseation studies
UR - http://www.scopus.com/inward/record.url?scp=85048925642&partnerID=8YFLogxK
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 -