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 Hoentjen; Mark Löwenberg; Bas Oldenburg; Marieke J. Pierik; Andrea E. Vander Meulen-De Jong; C. Janneke Van Der Woude; Marijn C. Visschedijk; The International IBD Genetics Consortium; Mark Lathrop; Jean Pierre Hugot; Rinse K. Weersma; Martine De Vos; Denis Franchimont; Severine Vermeire; Michiaki Kubo; Edouard Louis; Michel Georges

doi:10.1038/s41467-018-04365-8

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, The International IBD Genetics Consortium, Mark Lathrop, Jean Pierre Hugot, Rinse K. Weersma, Martine De Vos, Denis Franchimont, Severine Vermeire, Michiaki Kubo, Edouard Louis, Michel Georges

Research output: Contribution to journal › Article › Research › peer-review

142 Citations (Scopus)

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 language	English
Article number	2427
Number of pages	18
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04365-8
Publication status	Published - 1 Dec 2018
Externally published	Yes

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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., ... Georges, M. (2018). IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nature Communications, 9(1), Article 2427. https://doi.org/10.1038/s41467-018-04365-8

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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.",

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year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-04365-8",

language = "English",

volume = "9",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Momozawa, Y, Dmitrieva, J, Théâtre, E, Deffontaine, V, Rahmouni, S, Charloteaux, B, Crins, F, Docampo, E, Elansary, M, Gori, AS, Lecut, C, Mariman, R, Mni, M, Oury, C, Altukhov, I, Alexeev, D, Aulchenko, Y, Amininejad, L, Bouma, G, Hoentjen, F, Löwenberg, M, Oldenburg, B, Pierik, MJ, Vander Meulen-De Jong, AE, Van Der Woude, CJ, Visschedijk, MC, The International IBD Genetics Consortium, Lathrop, M, Hugot, JP, Weersma, RK, De Vos, M, Franchimont, D, Vermeire, S, Kubo, M, Louis, E & Georges, M 2018, 'IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes', Nature Communications, vol. 9, no. 1, 2427. https://doi.org/10.1038/s41467-018-04365-8

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'Amato, Mauro

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.

PY - 2018/12/1

Y1 - 2018/12/1

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.

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 -

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

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