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

Lookup NU author(s): Dr John Mansfield

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Abstract

© 2018 The Author(s).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.

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Author(s): Momozawa Y, Dmitrieva J, Theatre E, Deffontaine V, Rahmouni S, Charloteaux B, Crins F, Docampo E, Elansary M, Gori A-S, Lecut C, Mariman R, Mni M, Oury C, Altukhov I, Alexeev D, Aulchenko Y, Amininejad L, Bouma G, Hoentjen F, Lowenberg M, Oldenburg B, Pierik MJ, Vander Meulen-De Jong AE, Van Der Woude CJ, Visschedijk MC, Lathrop M, Hugot J-P, Weersma RK, De Vos M, Franchimont D, Vermeire S, Kubo M, Louis E, Georges M, Abraham C, Achkar J-P, 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, Buning C, Chew A, Cho JH, Cleynen I, Cohain A, Croft A, Daly MJ, D'Amato M, Danese S, De 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, Van Limbergen J, 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, Nothen M, Oikonomou I, Palmieri O, Parkes M, Phillips A, Ponsioen CY, Potocnik U, Prescott NJ, Proctor DD, Radford-Smith G, Rahier J-F, 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, Van Sommeren S, Vasiliauskas E, Verspaget HW, Walters T, Wang K, Wang M-H, Wei Z, Whiteman D, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zhang B, Zhang CK, Zhang H, Zhang W, Zhao H, Zhao ZZ

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2018

Volume: 9

Issue: 1

Online publication date: 21/06/2018

Acceptance date: 24/04/2018

Date deposited: 03/07/2018

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41467-018-04365-8

DOI: 10.1038/s41467-018-04365-8

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