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

Yukihide Momozawa, Julia Dmitrieva, Emilie Theatre, Valerie Deffontaine, Souad Rahmouni, Benoit Charloteaux, Francois Crins, Elisa Docampo, Mahmoud Elansary, Ann-Stephan Gori, Christelle Lecut, Rob Mariman, Myriam Mni, Cecile Oury, Ilya Altukhov, Dmitry Alexeev, Yuri Aulchenko, Leila Amininejad, Gerd Bouma, Frank HoentjenMark Lowenberg, 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, Stephan Brand, Dirk De Jong, Hu Zhang, Int IBD Genetics Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.
Original languageEnglish
Article number2427
Number of pages18
JournalNature Communications
Volume9
DOIs
Publication statusPublished - 21 Jun 2018

Keywords

  • INFLAMMATORY-BOWEL-DISEASE
  • GENOME-WIDE ASSOCIATION
  • QUANTITATIVE TRAIT LOCUS
  • RARE VARIANTS
  • LOW-FREQUENCY
  • CODING VARIANTS
  • SEQUENCING DATA
  • CROHNS-DISEASE
  • COMPLEX TRAITS
  • SUSCEPTIBILITY
  • Humans
  • Middle Aged
  • Male
  • Gene Expression Profiling
  • Multifactorial Inheritance
  • Aged, 80 and over
  • Adult
  • Female
  • Crohn Disease/genetics
  • Genetic Predisposition to Disease
  • Genetic Association Studies
  • Genotype
  • Sequence Analysis, DNA
  • Aged
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Cohort Studies
  • Inflammatory Bowel Diseases/genetics

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