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Disease variants alter transcription factor levels and methylation of their binding sites

View ORCID ProfileMarc Jan Bonder, View ORCID ProfileRené Luijk, View ORCID ProfileDaria V. Zhernakova, View ORCID ProfileMatthijs Moed, View ORCID ProfilePatrick Deelen, View ORCID ProfileMartijn Vermaat, View ORCID ProfileMaarten van Iterson, View ORCID ProfileFreerk van Dijk, View ORCID ProfileMichiel van Galen, View ORCID ProfileJan Bot, View ORCID ProfileRoderick C. Slieker, View ORCID ProfileP. Mila Jhamai, View ORCID ProfileMichael Verbiest, View ORCID ProfileH. Eka D. Suchiman, View ORCID ProfileMarijn Verkerk, View ORCID ProfileRuud van der Breggen, View ORCID ProfileJeroen van Rooij, View ORCID ProfileNico Lakenberg, View ORCID ProfileWibowo Arindrarto, View ORCID ProfileSzymon M. Kielbasa, View ORCID ProfileIris Jonkers, View ORCID ProfilePeter van ’t Hof, View ORCID ProfileIrene Nooren, View ORCID ProfileMarian Beekman, View ORCID ProfileJoris Deelen, View ORCID ProfileDiana van Heemst, View ORCID ProfileAlexandra Zhernakova, View ORCID ProfileEttje F. Tigchelaar, View ORCID ProfileMorris A. Swertz, View ORCID ProfileAlbert Hofman, View ORCID ProfileAndré G. Uitterlinden, 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 ProfileLeonard H. van den Berg, View ORCID ProfileErik. W van Zwet, View ORCID ProfileHailiang Mei, View ORCID ProfileMathieu Lemire, View ORCID ProfileThomas J. Hudson, the BIOS Consortium, View ORCID ProfileP. Eline Slagboom, View ORCID ProfileCisca Wijmenga, View ORCID ProfileJan H. Veldink, View ORCID ProfileMarleen M.J. van Greevenbroek, View ORCID ProfileCornelia M. van Duijn, View ORCID ProfileDorret I. Boomsma, View ORCID ProfileAaron Isaacs, View ORCID ProfileRick Jansen, View ORCID ProfileJoyce B.J. van Meurs, View ORCID ProfilePeter A.C. ’t Hoen, View ORCID ProfileLude Franke, View ORCID ProfileBastiaan T. Heijmans
doi: https://doi.org/10.1101/033084
Marc Jan Bonder
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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René Luijk
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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  • ORCID record for René Luijk
Daria V. Zhernakova
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Matthijs Moed
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Patrick Deelen
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
3Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Martijn Vermaat
4Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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Maarten van Iterson
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Freerk van Dijk
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
3Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Michiel van Galen
3Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Jan Bot
5SURFsara, Amsterdam, The Netherlands
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Roderick C. Slieker
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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P. Mila Jhamai
6Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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Michael Verbiest
3Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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H. Eka D. Suchiman
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Marijn Verkerk
6Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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Ruud van der Breggen
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Jeroen van Rooij
6Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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Nico Lakenberg
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Wibowo Arindrarto
8Medical Statistics Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Szymon M. Kielbasa
7Sequence Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
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Iris Jonkers
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Peter van ’t Hof
7Sequence Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
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Irene Nooren
5SURFsara, Amsterdam, The Netherlands
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Marian Beekman
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Joris Deelen
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Diana van Heemst
9Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands
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Alexandra Zhernakova
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Ettje F. Tigchelaar
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Morris A. Swertz
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
3Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Albert Hofman
10Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands
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André G. Uitterlinden
6Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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René Pool
11Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Jenny van Dongen
11Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Jouke J. Hottenga
11Department of Biological Psychology, VU University 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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Leonard H. van den Berg
13Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
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Erik. W van Zwet
8Medical Statistics Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Hailiang Mei
7Sequence Analysis Support Core, Leiden University Medical Center, Leiden, The Netherlands
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Mathieu Lemire
14Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3
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Thomas J. Hudson
14Ontario Institute for Cancer Research, Toronto, Ontario, Canada M5G 0A3
15Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada M5S 1A1
16Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S 1A1
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P. Eline Slagboom
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Cisca Wijmenga
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Jan H. Veldink
13Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, 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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Cornelia M. van Duijn
17Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands
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Dorret I. Boomsma
11Department of Biological Psychology, VU University Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Aaron Isaacs
17Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, The Netherlands
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Rick Jansen
18Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, The Netherlands
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Joyce B.J. van Meurs
6Department of Internal Medicine, ErasmusMC, Rotterdam, The Netherlands
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  • ORCID record for Joyce B.J. van Meurs
Peter A.C. ’t Hoen
4Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
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  • ORCID record for Peter A.C. ’t Hoen
Lude Franke
1Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands
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Bastiaan T. Heijmans
2Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands
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Abstract

Most disease associated genetic risk factors are non-coding, making it challenging to design experiments to understand their functional consequences1,2. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer downstream effects of disease variants but the large majority remains unexplained.3,4. The analysis of DNA methylation, a key component of the epigenome5, offers highly complementary data on the regulatory potential of genomic regions6,7. However, a large-scale, combined analysis of methylome and transcriptome data to infer downstream effects of disease variants is lacking. Here, we show that disease variants have wide-spread effects on DNA methylation in trans that likely reflect the downstream effects on binding sites of cis-regulated transcription factors. Using data on 3,841 Dutch samples, we detected 272,037 independent cis-meQTLs (FDR < 0.05) and identified 1,907 trait-associated SNPs that affect methylation levels of 10,141 different CpG sites in trans (FDR < 0.05), an eight-fold increase in the number downstream effects that was known from trans-eQTL studies3,8,9. Trans-meQTL CpG sites are enriched for active regulatory regions, being correlated with gene expression and overlap with Hi-C determined interchromosomal contacts10,11. We detected many trans-meQTL SNPs that affect expression levels of nearby transcription factors (including NFKB1, CTCF and NKX2–3), while the corresponding trans-meQTL CpG sites frequently coincide with its respective binding site. Trans-meQTL mapping therefore provides a strategy for identifying and better understanding downstream functional effects of many disease-associated variants.

Footnotes

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Copyright 
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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Disease variants alter transcription factor levels and methylation of their binding sites
Marc Jan Bonder, René Luijk, Daria V. Zhernakova, Matthijs Moed, Patrick Deelen, Martijn Vermaat, Maarten van Iterson, Freerk van Dijk, Michiel van Galen, Jan Bot, Roderick C. Slieker, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Wibowo Arindrarto, Szymon M. Kielbasa, Iris Jonkers, Peter van ’t Hof, Irene Nooren, Marian Beekman, Joris Deelen, Diana van Heemst, Alexandra Zhernakova, Ettje F. Tigchelaar, Morris A. Swertz, Albert Hofman, André G. Uitterlinden, René Pool, Jenny van Dongen, Jouke J. Hottenga, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Leonard H. van den Berg, Erik. W van Zwet, Hailiang Mei, Mathieu Lemire, Thomas J. Hudson, the BIOS Consortium, P. Eline Slagboom, Cisca Wijmenga, Jan H. Veldink, Marleen M.J. van Greevenbroek, Cornelia M. van Duijn, Dorret I. Boomsma, Aaron Isaacs, Rick Jansen, Joyce B.J. van Meurs, Peter A.C. ’t Hoen, Lude Franke, Bastiaan T. Heijmans
bioRxiv 033084; doi: https://doi.org/10.1101/033084
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Disease variants alter transcription factor levels and methylation of their binding sites
Marc Jan Bonder, René Luijk, Daria V. Zhernakova, Matthijs Moed, Patrick Deelen, Martijn Vermaat, Maarten van Iterson, Freerk van Dijk, Michiel van Galen, Jan Bot, Roderick C. Slieker, P. Mila Jhamai, Michael Verbiest, H. Eka D. Suchiman, Marijn Verkerk, Ruud van der Breggen, Jeroen van Rooij, Nico Lakenberg, Wibowo Arindrarto, Szymon M. Kielbasa, Iris Jonkers, Peter van ’t Hof, Irene Nooren, Marian Beekman, Joris Deelen, Diana van Heemst, Alexandra Zhernakova, Ettje F. Tigchelaar, Morris A. Swertz, Albert Hofman, André G. Uitterlinden, René Pool, Jenny van Dongen, Jouke J. Hottenga, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Leonard H. van den Berg, Erik. W van Zwet, Hailiang Mei, Mathieu Lemire, Thomas J. Hudson, the BIOS Consortium, P. Eline Slagboom, Cisca Wijmenga, Jan H. Veldink, Marleen M.J. van Greevenbroek, Cornelia M. van Duijn, Dorret I. Boomsma, Aaron Isaacs, Rick Jansen, Joyce B.J. van Meurs, Peter A.C. ’t Hoen, Lude Franke, Bastiaan T. Heijmans
bioRxiv 033084; doi: https://doi.org/10.1101/033084

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