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Nat Genet. 2017 Jan;49(1):131-138. doi: 10.1038/ng.3721. Epub 2016 Dec 5.

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

Author information

1
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
2
Molecular Epidemiology Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
3
University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, the Netherlands.
4
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
5
SURFsara, Amsterdam, the Netherlands.
6
Department of Internal Medicine, ErasmusMC, Rotterdam, the Netherlands.
7
Medical Statistics Section, Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
8
Sequence Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands.
9
Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.
10
Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.
11
Department of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.
12
Department of Internal Medicine, Maastricht University Medical Center, Maastricht, the Netherlands.
13
School for Cardiovascular Diseases (CARIM), Maastricht University Medical Center, Maastricht, the Netherlands.
14
Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
15
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
16
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
17
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
18
Genetic Epidemiology Unit, Department of Epidemiology, ErasmusMC, Rotterdam, the Netherlands.
19
Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, the Netherlands.
20
Department of Psychiatry, VU University Medical Center, Neuroscience Campus Amsterdam, Amsterdam, the Netherlands.

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.

PMID:
27918535
DOI:
10.1038/ng.3721
[Indexed for MEDLINE]

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