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 KielbasaIris 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, J. 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, Yang Li, Mathieu Lemire, Thomas J Hudson, P. Eline Slagboom, Cisca Wijmenga, Jan H Veldink, Marleen J. Van Greevenbroek, Cornelia M van Duijn, Dorret I Boomsma, Aaron Isaacs, BIOS Consortium

Research output: Contribution to JournalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalNature Genetics
Volume49
Issue number1
DOIs
Publication statusPublished - Jan 2017

Keywords

  • Journal Article

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