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

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

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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.
Original languageEnglish
Article number2427
Pages (from-to)-
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018
Externally publishedYes

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Momozawa, Y., Dmitrieva, J., Théâtre, 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., ... Zhao, Z. Z. (2018). IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nature Communications, 9(1), -. [2427]. https://doi.org/10.1038/s41467-018-04365-8