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Hypothesis-free identification of modulators of genetic risk factors

Daria V. Zhernakova, View ORCID ProfilePatrick Deelen, View ORCID ProfileMartijn Vermaat, View ORCID ProfileMaarten van Iterson, View ORCID ProfileMichiel van Galen, View ORCID ProfileWibowo Arindrarto, View ORCID ProfilePeter van ‘t Hof, View ORCID ProfileHailiang Mei, View ORCID ProfileFreerk van Dijk, View ORCID ProfileHarm-Jan Westra, View ORCID ProfileMarc Jan Bonder, View ORCID ProfileJeroen van Rooij, View ORCID ProfileMarijn Verkerk, View ORCID ProfileP. Mila Jhamai, View ORCID ProfileMatthijs Moed, View ORCID ProfileSzymon M. Kielbasa, View ORCID ProfileJan Bot, View ORCID ProfileIrene Nooren, View ORCID ProfileRené Pool, View ORCID ProfileJenny van Dongen, View ORCID ProfileJouke J. Hottenga, View ORCID ProfileCoen D.A. Stehouwer, View ORCID ProfileCarla J.H. van der Kallen, View ORCID ProfileCasper G. Schalkwijk, View ORCID ProfileAlexandra Zhernakova, View ORCID ProfileYang Li, View ORCID ProfileEttje F. Tigchelaar, View ORCID ProfileMarian Beekman, View ORCID ProfileJoris Deelen, View ORCID ProfileDiana van Heemst, View ORCID ProfileLeonard H. van den Berg, View ORCID ProfileAlbert Hofman, View ORCID ProfileAndré G. Uitterlinden, View ORCID ProfileMarleen M.J. van Greevenbroek, View ORCID ProfileJan H. Veldink, View ORCID ProfileDorret I. Boomsma, View ORCID ProfileCornelia M. van Duijn, View ORCID ProfileCisca Wijmenga, View ORCID ProfileP. Eline Slagboom, View ORCID ProfileMorris A. Swertz, View ORCID ProfileAaron Isaacs, View ORCID ProfileJoyce B.J. van Meurs, View ORCID ProfileRick Jansen, View ORCID ProfileBastiaan T. Heijmans, View ORCID ProfilePeter A.C. ‘t Hoen, View ORCID ProfileLude Franke
doi: https://doi.org/10.1101/033217
Daria V. Zhernakova
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
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Patrick Deelen
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
2University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands
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Martijn Vermaat
3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Maarten van Iterson
4Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
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  • ORCID record for Maarten van Iterson
Michiel van Galen
3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Wibowo Arindrarto
5Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands
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Peter van ‘t Hof
5Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands
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Hailiang Mei
5Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands
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Freerk van Dijk
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
2University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands
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Harm-Jan Westra
6Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, USA
7Partners Center for Personalized Genetic Medicine, Boston, USA
8Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, USA
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Marc Jan Bonder
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
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Jeroen van Rooij
9Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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Marijn Verkerk
9Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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  • ORCID record for Marijn Verkerk
P. Mila Jhamai
9Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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  • ORCID record for P. Mila Jhamai
Matthijs Moed
4Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
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Szymon M. Kielbasa
4Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
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Jan Bot
10SURFsara, Amsterdam, the Netherlands
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  • ORCID record for Jan Bot
Irene Nooren
10SURFsara, Amsterdam, the Netherlands
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  • ORCID record for Irene Nooren
René Pool
11Department of Biological Psychology, VU Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands
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Jenny van Dongen
11Department of Biological Psychology, VU Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands
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Jouke J. Hottenga
11Department of Biological Psychology, VU Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands
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Coen D.A. Stehouwer
12Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
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Carla J.H. van der Kallen
12Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
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Casper G. Schalkwijk
12Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
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Alexandra Zhernakova
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
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Yang Li
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
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Ettje F. Tigchelaar
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
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Marian Beekman
4Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
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Joris Deelen
4Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
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Diana van Heemst
13Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
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Leonard H. van den Berg
14Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
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  • ORCID record for Leonard H. van den Berg
Albert Hofman
15Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands
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André G. Uitterlinden
9Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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Marleen M.J. van Greevenbroek
12Department of Internal Medicine and School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands
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Jan H. Veldink
16Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
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Dorret I. Boomsma
11Department of Biological Psychology, VU Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands
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Cornelia M. van Duijn
17Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands
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  • ORCID record for Cornelia M. van Duijn
Cisca Wijmenga
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
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P. Eline Slagboom
4Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
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Morris A. Swertz
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
2University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands
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Aaron Isaacs
17Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands
18CARIM School for Cardiovascular Diseases and Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands
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Joyce B.J. van Meurs
9Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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  • ORCID record for Joyce B.J. van Meurs
Rick Jansen
19Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands
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Bastiaan T. Heijmans
4Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands
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Peter A.C. ‘t Hoen
3Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
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Lude Franke
1University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands
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  • ORCID record for Lude Franke
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Abstract

Genetic risk factors often localize in non-coding regions of the genome with unknown effects on disease etiology. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying the association of genetic risk factors with disease. More mechanistic insights can be derived from knowledge of the context, such as cell type or the activity of signaling pathways, influencing the nature and strength of eQTLs. Here, we generated peripheral blood RNA-seq data from 2,116 unrelated Dutch individuals and systematically identified these context-dependent eQTLs using a hypothesis-free strategy that does not require prior knowledge on the identity of the modifiers. Out of the 23,060 significant cis-regulated genes (false discovery rate < 0.05), 2,743 genes (12%) show context-dependent eQTL effects. The majority of those were influenced by cell type composition, revealing eQTLs that are particularly strong in cell types such as CD4+ T-cells, erythrocytes, and even lowly abundant eosinophils. A set of 145 cis-eQTLs were influenced by the activity of the type I interferon signaling pathway and we identified several cis-eQTLs that are modulated by specific transcription factors that bind to the eQTL SNPs. This demonstrates that large-scale eQTL studies in unchallenged individuals can complement perturbation experiments to gain better insight in regulatory networks and their stimuli.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Hypothesis-free identification of modulators of genetic risk factors
Daria V. Zhernakova, Patrick Deelen, Martijn Vermaat, Maarten van Iterson, Michiel van Galen, Wibowo Arindrarto, Peter van ‘t Hof, Hailiang Mei, Freerk van Dijk, Harm-Jan Westra, Marc Jan Bonder, Jeroen van Rooij, Marijn Verkerk, P. Mila Jhamai, Matthijs Moed, Szymon M. Kielbasa, Jan Bot, Irene Nooren, René Pool, Jenny van Dongen, Jouke J. Hottenga, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Alexandra Zhernakova, Yang Li, Ettje F. Tigchelaar, Marian Beekman, Joris Deelen, Diana van Heemst, Leonard H. van den Berg, Albert Hofman, André G. Uitterlinden, Marleen M.J. van Greevenbroek, Jan H. Veldink, Dorret I. Boomsma, Cornelia M. van Duijn, Cisca Wijmenga, P. Eline Slagboom, Morris A. Swertz, Aaron Isaacs, Joyce B.J. van Meurs, Rick Jansen, Bastiaan T. Heijmans, Peter A.C. ‘t Hoen, Lude Franke
bioRxiv 033217; doi: https://doi.org/10.1101/033217
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Hypothesis-free identification of modulators of genetic risk factors
Daria V. Zhernakova, Patrick Deelen, Martijn Vermaat, Maarten van Iterson, Michiel van Galen, Wibowo Arindrarto, Peter van ‘t Hof, Hailiang Mei, Freerk van Dijk, Harm-Jan Westra, Marc Jan Bonder, Jeroen van Rooij, Marijn Verkerk, P. Mila Jhamai, Matthijs Moed, Szymon M. Kielbasa, Jan Bot, Irene Nooren, René Pool, Jenny van Dongen, Jouke J. Hottenga, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Alexandra Zhernakova, Yang Li, Ettje F. Tigchelaar, Marian Beekman, Joris Deelen, Diana van Heemst, Leonard H. van den Berg, Albert Hofman, André G. Uitterlinden, Marleen M.J. van Greevenbroek, Jan H. Veldink, Dorret I. Boomsma, Cornelia M. van Duijn, Cisca Wijmenga, P. Eline Slagboom, Morris A. Swertz, Aaron Isaacs, Joyce B.J. van Meurs, Rick Jansen, Bastiaan T. Heijmans, Peter A.C. ‘t Hoen, Lude Franke
bioRxiv 033217; doi: https://doi.org/10.1101/033217

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