title: Disease variants alter transcription factor levels and methylation of their binding sites.
abstract: Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer the downstream effects of disease-associated variants, but most of these variants remain unexplained. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. Here we show that disease-associated variants have widespread effects on DNA methylation in trans that likely reflect differential occupancy of trans binding sites by cis-regulated transcription factors. Using multiple omics data sets from 3,841 Dutch individuals, we identified 1,907 established trait-associated SNPs that affect the methylation levels of 10,141 different CpG sites in trans (false discovery rate (FDR) < 0.05). These included SNPs that affect both the expression of a nearby transcription factor (such as NFKB1, CTCF and NKX2-3) and methylation of its respective binding site across the genome. Trans methylation QTLs effectively expose the downstream effects of disease-associated variants.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Marc Jan
authors.initials: MJ
authors.lastname: Bonder
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: René
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authors.lastname: Luijk
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Daria V
authors.initials: DV
authors.lastname: Zhernakova
authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Matthijs
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authors.lastname: Moed
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Patrick
authors.identifier: 0000-0002-5654-3966
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authors.lastname: Deelen
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Martijn
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authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Maarten
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authors.lastname: van Iterson
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Freerk
authors.initials: F
authors.lastname: van Dijk
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
authors.forename: Michiel
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authors.lastname: van Galen
authors.affiliation: SURFsara, Amsterdam, the Netherlands.
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authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.identifier: 0000-0003-0961-9152
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authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
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authors.lastname: Jhamai
authors.affiliation: University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
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authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
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authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
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authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Medical Statistics Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands.
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authors.initials: SM
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
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authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.initials: D
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
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authors.lastname: Zhernakova
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Ettje F
authors.initials: EF
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.|University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
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authors.affiliation: Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.
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authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
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authors.affiliation: Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
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authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.|School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
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authors.initials: CD
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authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.|School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
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authors.initials: CJ
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authors.affiliation: Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.|School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
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authors.initials: CG
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authors.affiliation: Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
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authors.identifier: 0000-0002-1376-4849
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authors.affiliation: School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.|Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.|Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands.
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authors.affiliation: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
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authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
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mesh_terms: D001665:Binding Sites; D015331:Cohort Studies; D019175:DNA Methylation; D004194:Disease / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors