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

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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 similar to 9720 regulatory modules, of which similar to 3000 operate in multiple tissues and similar to 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.
Keywords
INFLAMMATORY-BOWEL-DISEASE, GENOME-WIDE ASSOCIATION, QUANTITATIVE TRAIT, LOCUS, RARE VARIANTS, LOW-FREQUENCY, CODING VARIANTS, SEQUENCING DATA, CROHNS-DISEASE, COMPLEX TRAITS, SUSCEPTIBILITY

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Chicago
Momozawa, Yukihide, Julia Dmitrieva, Emilie Theatre, Valerie Deffontaine, Souad Rahmouni, Benoit Charloteaux, Francois Crins, et al. 2018. “IBD Risk Loci Are Enriched in Multigenic Regulatory Modules Encompassing Putative Causative Genes.” Nature Communications 9.
APA
Momozawa, Y., Dmitrieva, J., Theatre, E., Deffontaine, V., Rahmouni, S., Charloteaux, B., Crins, F., et al. (2018). IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. NATURE COMMUNICATIONS, 9.
Vancouver
1.
Momozawa Y, Dmitrieva J, Theatre E, Deffontaine V, Rahmouni S, Charloteaux B, et al. IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. NATURE COMMUNICATIONS. 2018;9.
MLA
Momozawa, Yukihide, Julia Dmitrieva, Emilie Theatre, et al. “IBD Risk Loci Are Enriched in Multigenic Regulatory Modules Encompassing Putative Causative Genes.” NATURE COMMUNICATIONS 9 (2018): n. pag. Print.
@article{8582997,
  abstract     = {GWAS have identified {\textrangle}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 similar to 9720 regulatory modules, of which similar to 3000 operate in multiple tissues and similar to 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 {\textrangle}= 10-fold larger sample sizes will be required to demonstrate the causality of individual genes using this approach.},
  articleno    = {2427},
  author       = {Momozawa, Yukihide and Dmitrieva, Julia and Theatre, Emilie and Deffontaine, Valerie and Rahmouni, Souad and Charloteaux, Benoit and Crins, Francois and Docampo, Elisa and Elansary, Mahmoud and Gori, Ann-Stephan and Lecut, Christelle and Mariman, Rob and Mni, Myriam and Oury, Cecile and Altukhov, Ilya and Alexeev, Dmitry and Aulchenko, Yuri and Amininejad, Leila and Bouma, Gerd and Hoentjen, Frank and Lowenberg, Mark and Oldenburg, Bas and Pierik, Marieke J and vander Meulen-de Jong, Andrea E and van der Woude, C Janneke and Visschedijk, Marijn C and Lathrop, Mark and Hugot, Jean-Pierre and Weersma, Rinse K and De Vos, Martine and Franchimont, Denis and Vermeire, Severine and Kubo, Michiaki and Louis, Edouard and Georges, Michel and Abraham, Clara and Achkar, Jean-Paul and Ahmad, Tariq and Ananthakrishnan, Ashwin N and Andersen, Vibeke and Anderson, Carl A and Andrews, Jane M and Annese, Vito and Aumais, Guy and Baidoo, Leonard and Baldassano, Robert N and Bampton, Peter A and Barclay, Murray and Barrett, Jeffrey C and Bayless, Theodore M and Bethge, Johannes and Bitton, Alain and Boucher, Gabrielle and Brand, Stephan and Brandt, Berenice and Brant, Steven R and Buening, Carsten and Chew, Angela and Cho, Judy H and Cleynen, Isabelle and Cohain, Ariella and Croft, Anthony and Daly, Mark J and D'Amato, Mauro and Danese, Silvio and De Jong, Dirk and Denapiene, Goda and Denson, Lee A and Devaney, Kathy L. and Dewit, Olivier and D'Inca, Renata and Dubinsky, Marla and Duerr, Richard H and Edwards, Cathryn and Ellinghaus, David and Essers, Jonah and Ferguson, Lynnette R and Festen, Eleonora A and Fleshner, Philip and Florin, Tim and Franke, Andre and Fransen, Karin and Gearry, Richard and Gieger, Christian and Glas, Juergen and Goyette, Philippe and Green, Todd and Griffiths, Anne M and Guthery, Stephen L and Hakonarson, Hakon and Halfvarson, Jonas and Hanigan, Katherine and Haritunians, Talin and Hart, Ailsa and Hawkey, Chris and Hayward, Nicholas K and Hedl, Matija and Henderson, Paul and Hu, Xinli and Huang, Hailiang and Hui, Ken Y and Imielinski, Marcin and Ippoliti, Andrew and Jonaitis, Laimas and Jostins, Luke and Karlsen, Tom H and Kennedy, Nicholas A and Khan, Mohammed Azam and Kiudelis, Gediminas and Krishnaprasad, Krupa and Kugathasan, Subra and Kupcinskas, Limas and Latiano, Anna and Laukens, Debby and Lawrance, Ian C and Lee, James C and Lees, Charlie W and Leja, Marcis and Van Limbergen, Johan and Lionetti, Paolo and Liu, Jimmy Z and Mahy, Gillian and Mansfield, John and Massey, Dunecan and Mathew, Christopher G and McGovern, Dermot P.B and Milgrom, Raquel and Mitrovic, Mitja and Montgomery, Grant W and Mowat, Craig and Newman, William and Ng, Aylwin and Ng, Siew C and Ng, Sok Meng Evelyn and Nikolaus, Susanna and Ning, Kaida and Noethen, Markus and Oikonomou, Ioloannis and Palmieri, Orazio and Parkes, Miles and Phillips, Anne and Ponsioen, Cyriel Y and Potocnik, Uros and Prescott, Natalie J and Proctor, Deborah D and Radford-Smith, Graham and Rahier, Jean-Francois and Raychaudhuri, Soumya and Regueiro, Miguel and Rieder, Florian and Rioux, John D and Ripke, Stephan and Roberts, Rebecca and Russell, Richard K and Sanderson, Jeremy D and Sans, Miguel and Satsangi, Jack and Schadt, Eric E and Schreiber, Stefan and Schulte, Dominik and Schumm, L Philip and Scott, Regan and Seielstad, Mark and Sharma, Yashoda and Silverberg, Mark S and Simms, Lisa A. and Skieceviciene, Jurgita and Spain, Sarah L and Steinhart, A Hillary and Stempak, Joanne M and Stronati, Laura and Sventoraityte, Jurgita and Targan, Stephan R and Taylor, Kirstin M and ter Velde, Anje and Torkvist, Leif and Tremelling, Mark and van Sommeren, Suzanne and Vasiliauskas, Eric and Verspaget, Hein W and Walters, Thomas and Wang, Kai and Wang, Ming-Hsi and Wei, Zhi and Whiteman, David and Wijmenga, Cisca and Wilson, David C and Winkelmann, Juliane and Xavier, Ramnik J and Zhang, Bin and Zhang, Clarence K and Zhang, Hu and Zhang, Wei and Zhao, Hongyu and Zhao, Zhen Z},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  language     = {eng},
  pages        = {18},
  title        = {IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes},
  url          = {http://dx.doi.org/10.1038/s41467-018-04365-8},
  volume       = {9},
  year         = {2018},
}

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