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Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations

Author

Listed:
  • Sarah Kim-Hellmuth

    (New York Genome Center
    Columbia University
    University of Bonn
    University of Bonn)

  • Matthias Bechheim

    (University of Bonn)

  • Benno Pütz

    (Max Planck Institute of Psychiatry)

  • Pejman Mohammadi

    (New York Genome Center
    Columbia University)

  • Yohann Nédélec

    (CHU Sainte-Justine Research Center
    University of Montreal)

  • Nicholas Giangreco

    (Columbia University)

  • Jessica Becker

    (University of Bonn
    University of Bonn)

  • Vera Kaiser

    (University of Bonn)

  • Nadine Fricker

    (University of Bonn
    University of Bonn)

  • Esther Beier

    (University of Bonn)

  • Peter Boor

    (University Clinic of RWTH Aachen)

  • Stephane E. Castel

    (New York Genome Center
    Columbia University)

  • Markus M. Nöthen

    (University of Bonn
    University of Bonn)

  • Luis B. Barreiro

    (CHU Sainte-Justine Research Center
    University of Montreal)

  • Joseph K. Pickrell

    (New York Genome Center
    Columbia University)

  • Bertram Müller-Myhsok

    (Max Planck Institute of Psychiatry
    Munich Cluster for Systems Neurology (SyNergy)
    University of Liverpool)

  • Tuuli Lappalainen

    (New York Genome Center
    Columbia University)

  • Johannes Schumacher

    (University of Bonn
    University of Bonn)

  • Veit Hornung

    (University of Bonn
    Ludwig-Maximilians-Universität Munich
    Ludwig-Maximilians-Universität Munich)

Abstract

The immune system plays a major role in human health and disease, and understanding genetic causes of interindividual variability of immune responses is vital. Here, we isolate monocytes from 134 genotyped individuals, stimulate these cells with three defined microbe-associated molecular patterns (LPS, MDP, and 5′-ppp-dsRNA), and profile the transcriptomes at three time points. Mapping expression quantitative trait loci (eQTL), we identify 417 response eQTLs (reQTLs) with varying effects between conditions. We characterize the dynamics of genetic regulation on early and late immune response and observe an enrichment of reQTLs in distal cis-regulatory elements. In addition, reQTLs are enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover reQTL effects in multiple GWAS loci and show a stronger enrichment for response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli in modifying genetic predisposition to disease.

Suggested Citation

  • Sarah Kim-Hellmuth & Matthias Bechheim & Benno Pütz & Pejman Mohammadi & Yohann Nédélec & Nicholas Giangreco & Jessica Becker & Vera Kaiser & Nadine Fricker & Esther Beier & Peter Boor & Stephane E. C, 2017. "Genetic regulatory effects modified by immune activation contribute to autoimmune disease associations," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00366-1
    DOI: 10.1038/s41467-017-00366-1
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    Cited by:

    1. Jianping Quan & Ming Yang & Xingwang Wang & Gengyuan Cai & Rongrong Ding & Zhanwei Zhuang & Shenping Zhou & Suxu Tan & Donglin Ruan & Jiajin Wu & Enqin Zheng & Zebin Zhang & Langqing Liu & Fanming Men, 2024. "Multi-omic characterization of allele-specific regulatory variation in hybrid pigs," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Antje Häder & Sascha Schäuble & Jan Gehlen & Nadja Thielemann & Benedikt C. Buerfent & Vitalia Schüller & Timo Hess & Thomas Wolf & Julia Schröder & Michael Weber & Kerstin Hünniger & Jürgen Löffler &, 2023. "Pathogen-specific innate immune response patterns are distinctly affected by genetic diversity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    3. Lei Li & Xuelian Ma & Ya Cui & Maxime Rotival & Wenyan Chen & Xudong Zou & Ruofan Ding & Yangmei Qin & Qixuan Wang & Lluis Quintana-Murci & Wei Li, 2023. "Immune-response 3′UTR alternative polyadenylation quantitative trait loci contribute to variation in human complex traits and diseases," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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