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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 Castel, Markus M. Nöthen, Luis B. Barreiro, Joseph K. Pickrell, Bertram Müller-Myhsok, Tuuli Lappalainen, Johannes Schumacher, Veit Hornung
doi: https://doi.org/10.1101/116376
Sarah Kim-Hellmuth
1New York Genome Center, New York, NY 10013, USA
2Department of Systems Biology, Columbia University, New York, NY 10032, USA
3Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany
4Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany
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Matthias Bechheim
5Institute of Molecular Medicine, University of Bonn, Bonn, 53127, Germany
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Benno Pütz
6Statistical Genetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany
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Pejman Mohammadi
1New York Genome Center, New York, NY 10013, USA
2Department of Systems Biology, Columbia University, New York, NY 10032, USA
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Yohann Nédélec
8CHU Sainte-Justine Research Center, Department of Genetics, Montreal, H3T 1C5, Canada
9University of Montreal, Department of Biochemistry, Montreal, H3C 3J7, Canada
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Nicholas Giangreco
2Department of Systems Biology, Columbia University, New York, NY 10032, USA
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Jessica Becker
3Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany
4Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany
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Vera Kaiser
5Institute of Molecular Medicine, University of Bonn, Bonn, 53127, Germany
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Nadine Fricker
3Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany
4Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany
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Esther Beier
5Institute of Molecular Medicine, University of Bonn, Bonn, 53127, Germany
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Peter Boor
7Institute of Pathology and Department of Nephrology, University Clinic of RWTH Aachen, Aachen, 52074, Germany
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Stephane Castel
1New York Genome Center, New York, NY 10013, USA
2Department of Systems Biology, Columbia University, New York, NY 10032, USA
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Markus M. Nöthen
3Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany
4Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany
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Luis B. Barreiro
8CHU Sainte-Justine Research Center, Department of Genetics, Montreal, H3T 1C5, Canada
10University of Montreal, Department of Pediatrics, Montreal, H3T 1C5, Canada
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Joseph K. Pickrell
1New York Genome Center, New York, NY 10013, USA
11Department of Biological Sciences, Columbia University, New York, NY, USA
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Bertram Müller-Myhsok
6Statistical Genetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany
12Munich Cluster for Systems Neurology (SyNergy), Munich, 80804, Germany
13Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GL, UK
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Tuuli Lappalainen
1New York Genome Center, New York, NY 10013, USA
2Department of Systems Biology, Columbia University, New York, NY 10032, USA
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Johannes Schumacher
3Institute of Human Genetics, University of Bonn, Bonn, 53127, Germany
4Department of Genomics, Life & Brain Center, University of Bonn, Bonn, 53127, Germany
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Veit Hornung
5Institute of Molecular Medicine, University of Bonn, Bonn, 53127, Germany
14Gene Center and Department of Biochemistry, Ludwig-Maximilians-University Munich, Munich, 81377, Germany
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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. We isolated monocytes from 134 genotyped individuals, stimulated the cells with three defined microbe-associated molecular patterns (LPS, MDP, and ppp-dsRNA), and profiled the transcriptome at three time points. After mapping expression quantitative trait loci (eQTL), we identified 417 response eQTLs (reQTLs) with differing effect between the conditions. We characterized the dynamics of genetic regulation on early and late immune response, and observed an enrichment of reQTLs in distal cis-regulatory elements. Response eQTLs are also enriched for recent positive selection with an evolutionary trend towards enhanced immune response. Finally, we uncover novel reQTL effects in multiple GWAS loci, and show a stronger enrichment of response than constant eQTLs in GWAS signals of several autoimmune diseases. This demonstrates the importance of infectious stimuli modifying genetic predisposition to disease.

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Posted March 13, 2017.
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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 Castel, Markus M. Nöthen, Luis B. Barreiro, Joseph K. Pickrell, Bertram Müller-Myhsok, Tuuli Lappalainen, Johannes Schumacher, Veit Hornung
bioRxiv 116376; doi: https://doi.org/10.1101/116376
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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 Castel, Markus M. Nöthen, Luis B. Barreiro, Joseph K. Pickrell, Bertram Müller-Myhsok, Tuuli Lappalainen, Johannes Schumacher, Veit Hornung
bioRxiv 116376; doi: https://doi.org/10.1101/116376

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