IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes
Authors: Momozawa Yukihide , Dmitrieva Julia , Théâtre 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 , Amininejad Leila , Bouma Gerd , Hoentjen Frank , Löwenberg Mark , Oldenburg Bas , Pierik Marieke J. , vander Meulen-de Jong Andrea E. , Janneke van der Woude C. , Visschedijk Marijn C. ,   The International IBD Genetics Consortium, Abraham Clara , Achkar Jean-Paul , Ahmad Tariq , Ananthakrishnan Ashwin N. , Andersen Vibeke , Anderson Carl A. , Andrews Jane M. , Annese Vito , Aumais Guy , Baidoo Leonard , Baldassano Robert N. , Bampton Peter A. , Barclay Murray , Barrett Jeffrey C. , Bayless Theodore M. , Bethge Johannes , Bitton Alain , Boucher Gabrielle , Brand Stephan , Brandt Berenice , Brant Steven R. , Büning Carsten , Chew Angela , Cho Judy H. , Cleynen Isabelle , Cohain Ariella , Croft Anthony , Daly Mark J. , D’Amato Mauro , Danese Silvio , Jong Dirk De , Denapiene Goda , Denson Lee A. , Devaney Kathy L. , Dewit Olivier , D’Inca Renata , Dubinsky Marla , Duerr Richard H. , Edwards Cathryn , Ellinghaus David , Essers Jonah , Ferguson Lynnette R. , Festen Eleonora A. , Fleshner Philip , Florin Tim , Franke Andre , Fransen Karin , Gearry Richard , Gieger Christian , Glas Jürgen , Goyette Philippe , Green Todd , Griffiths Anne M. , Guthery Stephen L. , Hakonarson Hakon , Halfvarson Jonas , Hanigan Katherine , Haritunians Talin , Hart Ailsa , Hawkey Chris , Hayward Nicholas K. , Hedl Matija , Henderson Paul , Hu Xinli , Huang Hailiang , Hui Ken Y. , Imielinski Marcin , Ippoliti Andrew , Jonaitis Laimas , Jostins Luke , Karlsen Tom H. , Kennedy Nicholas A. , Khan Mohammed Azam , Kiudelis Gediminas , Krishnaprasad Krupa , Kugathasan Subra , Kupcinskas Limas , Latiano Anna , Laukens Debby , Lawrance Ian C. , Lee James C. , Lees Charlie W. , Leja Marcis , Limbergen Johan Van , Lionetti Paolo , Liu Jimmy Z. , Mahy Gillian , Mansfield John , Massey Dunecan , Mathew Christopher G. , McGovern Dermot P. B. , Milgrom Raquel , Mitrovic Mitja , Montgomery Grant W. , Mowat Craig , Newman William , Ng Aylwin , Ng Siew C. , Ng Sok Meng Evelyn , Nikolaus Susanna , Ning Kaida , Nöthen Markus , Oikonomou Ioannis , Palmieri Orazio , Parkes Miles , Phillips Anne , Ponsioen Cyriel Y. , Potocnik Urõs , Prescott Natalie J. , Proctor Deborah D. , Radford-Smith Graham , Rahier Jean-Francois , Raychaudhuri Soumya , Regueiro Miguel , Rieder Florian , Rioux John D. , Ripke Stephan , Roberts Rebecca , Russell Richard K. , Sanderson Jeremy D. , Sans Miquel , Satsangi Jack , Schadt Eric E. , Schreiber Stefan , Schulte Dominik , Schumm L. Philip , Scott Regan , Seielstad Mark , Sharma Yashoda , Silverberg Mark S. , Simms Lisa A. , Skieceviciene Jurgita , Spain Sarah L. , Steinhart A. Hillary , Stempak Joanne M. , Stronati Laura , Sventoraityte Jurgita , Targan Stephan R. , Taylor Kirstin M. , ter Velde Anje , Torkvist Leif , Tremelling Mark , Sommeren Suzanne van , Vasiliauskas Eric , Verspaget Hein W. , Walters Thomas , Wang Kai , Wang Ming-Hsi , Wei Zhi , Whiteman David , Wijmenga Cisca , Wilson David C. , Winkelmann Juliane , Xavier Ramnik J. , Zhang Bin , Zhang Clarence K. , Zhang Hu , Zhang Wei , Zhao Hongyu , Zhao Zhen Z. , Lathrop Mark , Hugot Jean-Pierre , Weersma Rinse K. , De Vos Martine , Franchimont Denis , Vermeire Severine , Kubo Michiaki , Louis Edouard , Georges Michel 
Published: June 2018

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.