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

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. Castel, Markus M. Nöthen, Luis B. Barreiro, Joseph K. Pickrell, Bertram Müller-Myhsok, Tuuli Lappalainen (), Johannes Schumacher () and Veit Hornung
Additional contact information
Sarah Kim-Hellmuth: New York Genome Center
Matthias Bechheim: University of Bonn
Benno Pütz: Max Planck Institute of Psychiatry
Pejman Mohammadi: New York Genome Center
Yohann Nédélec: CHU Sainte-Justine Research Center
Nicholas Giangreco: Columbia University
Jessica Becker: University of Bonn
Vera Kaiser: University of Bonn
Nadine Fricker: University of Bonn
Esther Beier: University of Bonn
Peter Boor: University Clinic of RWTH Aachen
Stephane E. Castel: New York Genome Center
Markus M. Nöthen: University of Bonn
Luis B. Barreiro: CHU Sainte-Justine Research Center
Joseph K. Pickrell: New York Genome Center
Bertram Müller-Myhsok: Max Planck Institute of Psychiatry
Tuuli Lappalainen: New York Genome Center
Johannes Schumacher: University of Bonn
Veit Hornung: University of Bonn

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00366-1

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