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

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Listed:
  • Yukihide Momozawa

    (University of Liège (B34)
    RIKEN Center for Integrative Medical Science)

  • Julia Dmitrieva

    (University of Liège (B34))

  • Emilie Théâtre

    (University of Liège (B34))

  • Valérie Deffontaine

    (University of Liège (B34))

  • Souad Rahmouni

    (University of Liège (B34))

  • Benoît Charloteaux

    (University of Liège (B34))

  • François Crins

    (University of Liège (B34))

  • Elisa Docampo

    (University of Liège (B34))

  • Mahmoud Elansary

    (University of Liège (B34))

  • Ann-Stephan Gori

    (University of Liège (B34))

  • Christelle Lecut

    (University of Liège (B34))

  • Rob Mariman

    (University of Liège (B34))

  • Myriam Mni

    (University of Liège (B34))

  • Cécile Oury

    (University of Liège (B34))

  • Ilya Altukhov

    (Moscow Institute of Physics and Technology)

  • Dmitry Alexeev

    (Novosibirsk State University)

  • Yuri Aulchenko

    (PolyOmica
    Institute of Cytology and Genetics SD RAS
    University of Edinburgh)

  • Leila Amininejad

    (Université Libre de Bruxelles)

  • Gerd Bouma

    (VU University Medical Centre)

  • Frank Hoentjen

    (University Medical Centre St. Radboud)

  • Mark Löwenberg

    (Amsterdam Medical Centre)

  • Bas Oldenburg

    (University Medical Centre Utrecht)

  • Marieke J. Pierik

    (University Medical Centre Maastricht)

  • Andrea E. vander Meulen-de Jong

    (Leiden University Medical Centre)

  • C. Janneke van der Woude

    (Erasmus Medical Centre)

  • Marijn C. Visschedijk

    (University of Groningen and University Medical Center Groningen)

  • Mark Lathrop

    (McGill University Centre for Molecular and Computational Genomics)

  • Jean-Pierre Hugot

    (UMR 1149 INSERM/Université Paris-Diderot Sorbonne Paris-Cité, Assistance Publique Hôpitaux de Paris)

  • Rinse K. Weersma

    (University of Groningen and University Medical Center Groningen)

  • Martine Vos

    (University Hospital)

  • Denis Franchimont

    (Université Libre de Bruxelles)

  • Severine Vermeire

    (KU Leuven)

  • Michiaki Kubo

    (RIKEN Center for Integrative Medical Science)

  • Edouard Louis

    (University of Liège)

  • Michel Georges

    (University of Liège (B34))

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.

Suggested Citation

  • Yukihide Momozawa & Julia Dmitrieva & Emilie Théâtre & Valérie Deffontaine & Souad Rahmouni & Benoît Charloteaux & François Crins & Elisa Docampo & Mahmoud Elansary & Ann-Stephan Gori & Christelle Lec, 2018. "IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04365-8
    DOI: 10.1038/s41467-018-04365-8
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    Cited by:

    1. Jia Li & Alan J. Simmons & Caroline V. Hawkins & Sophie Chiron & Marisol A. Ramirez-Solano & Naila Tasneem & Harsimran Kaur & Yanwen Xu & Frank Revetta & Paige N. Vega & Shunxing Bao & Can Cui & Regin, 2024. "Identification and multimodal characterization of a specialized epithelial cell type associated with Crohn’s disease," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Arianna Landini & Irena Trbojević-Akmačić & Pau Navarro & Yakov A. Tsepilov & Sodbo Z. Sharapov & Frano Vučković & Ozren Polašek & Caroline Hayward & Tea Petrović & Marija Vilaj & Yurii S. Aulchenko &, 2022. "Genetic regulation of post-translational modification of two distinct proteins," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Ashley Budu-Aggrey & Anna Kilanowski & Maria K. Sobczyk & Suyash S. Shringarpure & Ruth Mitchell & Kadri Reis & Anu Reigo & Reedik Mägi & Mari Nelis & Nao Tanaka & Ben M. Brumpton & Laurent F. Thomas , 2023. "European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. Vasili Pankratov & Milyausha Yunusbaeva & Sergei Ryakhovsky & Maksym Zarodniuk & Bayazit Yunusbayev, 2022. "Prioritizing autoimmunity risk variants for functional analyses by fine-mapping mutations under natural selection," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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