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Nat Commun. 2018 Jun 21;9(1):2427. doi: 10.1038/s41467-018-04365-8.

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

Collaborators (160)

Abraham C, Achkar JP, Ahmad T, Ananthakrishnan AN, Andersen V, Anderson CA, Andrews JM, Annese V, Aumais G, Baidoo L, Baldassano RN, Bampton PA, Barclay M, Barrett JC, Bayless TM, Bethge J, Bitton A, Boucher G, Brand S, Brandt B, Brant SR, Büning C, Chew A, Cho JH, Cleynen I, Cohain A, Croft A, Daly MJ, D'Amato M, Danese S, Jong D, Denapiene G, Denson LA, Devaney KL, Dewit O, D'Inca R, Dubinsky M, Duerr RH, Edwards C, Ellinghaus D, Essers J, Ferguson LR, Festen EA, Fleshner P, Florin T, Franke A, Fransen K, Gearry R, Gieger C, Glas J, Goyette P, Green T, Griffiths AM, Guthery SL, Hakonarson H, Halfvarson J, Hanigan K, Haritunians T, Hart A, Hawkey C, Hayward NK, Hedl M, Henderson P, Hu X, Huang H, Hui KY, Imielinski M, Ippoliti A, Jonaitis L, Jostins L, Karlsen TH, Kennedy NA, Khan MA, Kiudelis G, Krishnaprasad K, Kugathasan S, Kupcinskas L, Latiano A, Laukens D, Lawrance IC, Lee JC, Lees CW, Leja M, Limbergen JV, Lionetti P, Liu JZ, Mahy G, Mansfield J, Massey D, Mathew CG, McGovern DPB, Milgrom R, Mitrovic M, Montgomery GW, Mowat C, Newman W, Ng A, Ng SC, Ng SME, Nikolaus S, Ning K, Nöthen M, Oikonomou I, Palmieri O, Parkes M, Phillips A, Ponsioen CY, Potocnik U, Prescott NJ, Proctor DD, Radford-Smith G, Rahier JF, Raychaudhuri S, Regueiro M, Rieder F, Rioux JD, Ripke S, Roberts R, Russell RK, Sanderson JD, Sans M, Satsangi J, Schadt EE, Schreiber S, Schulte D, Schumm LP, Scott R, Seielstad M, Sharma Y, Silverberg MS, Simms LA, Skieceviciene J, Spain SL, Steinhart AH, Stempak JM, Stronati L, Sventoraityte J, Targan SR, Taylor KM, Ter Velde A, Torkvist L, Tremelling M, Sommeren SV, Vasiliauskas E, Verspaget HW, Walters T, Wang K, Wang MH, Wei Z, Whiteman D, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zhang B, Zhang CK, Zhang H, Zhang W, Zhao H, Zhao ZZ.

Author information

1
Unit of Animal Genomics, WELBIO, GIGA-R & Faculty of Veterinary Medicine, University of Liège (B34), 1 Avenue de l'Hôpital, Liège, 4000, Belgium.
2
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Science, 1-7-22, Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan.
3
Laboratory of Thrombosis and Hemostasis, GIGA-R, University of Liège (B34), 1 Avenue de l'Hôpital, 4000, Liège, Belgium.
4
Moscow Institute of Physics and Technology, Institutskiy Pereulok 9, Dolgoprudny, 141700, Russian Federation.
5
Novosibirsk State University, Pirogova ave. 2, Novosibirsk, 630090, Russian Federation.
6
PolyOmica, Het Vlaggeschip 61, 's-Hertogenbosch, 5237 PA, The Netherlands.
7
Institute of Cytology and Genetics SD RAS, Lavrentyeva ave. 10, 630090, Novosibirsk, Russia.
8
Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Teviot Place, Edinburgh, EH8 9AG, UK.
9
Gastroentérologie Médicale, Faculté de Médicine, Université Libre de Bruxelles, Route de Lennik 808, Anderlecht, 1070, Belgium.
10
Department of Gastroenterology and Hepatology, VU University Medical Centre, Amsterdam, 1081 HV, The Netherlands.
11
Department of Gastroenterology and Hepatology, University Medical Centre St. Radboud, Nijmegen, 6525 GA, The Netherlands.
12
Department of Gastroenterology and Hepatology, Amsterdam Medical Centre, Amsterdam, 1105 AZ, The Netherlands.
13
Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, 3584 cX, Utrecht, The Netherlands.
14
Department of Gastroenterology and Hepatology, University Medical Centre Maastricht, Maastricht, 6229 HX, The Netherlands.
15
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, 2333 ZA, The Netherlands.
16
Department of Gastroenterology and Hepatology, Erasmus Medical Centre, Rotterdam, 3015 CE, The Netherlands.
17
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Hanzeplein 1, Groningen, 9713 GZ, The Netherlands.
18
McGill University Centre for Molecular and Computational Genomics, 740 Dr. Penfield Avenue, Montreal, H3A 0G1, QC, Canada.
19
UMR 1149 INSERM/Université Paris-Diderot Sorbonne Paris-Cité, Assistance Publique Hôpitaux de Paris, 48 Bd Sérurier, Paris, 75019, France.
20
Department of Gastroenterology, University Hospital, De Pintelaan 185, Gent, 9000, Belgium.
21
Translational Research in Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, UZ Herestraat 49, Leuven, 3000, Belgium.
22
CHU-Liège and Unit of Gastroenterology, GIGA-R & Faculty of Medicine, University of Liège, 1 Avenue de l'Hôpital, Liège, 4000, Belgium.
23
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.

Abstract

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.

PMID:
29930244
PMCID:
PMC6013502
DOI:
10.1038/s41467-018-04365-8
[Indexed for MEDLINE]
Free PMC Article

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