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 BoumaFrank Hoentjen, Mark 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

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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)1-18
Number of pages18
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 21 Jun 2018

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Cohort Studies
  • Crohn Disease/genetics
  • Female
  • Gene Expression Profiling
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Inflammatory Bowel Diseases/genetics
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Sequence Analysis, DNA

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  • 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., ... Georges, M. (2018). IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nature Communications, 9(1), 1-18. [2427]. https://doi.org/10.1038/s41467-018-04365-8