Disease variants alter transcription factor levels and methylation of their binding sites
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Publication date
2017-01
Authors
Bonder, Marc Jan
Luijk, René
Zhernakova, Daria V
Moed, Matthijs
Deelen, Patrick
Vermaat, Martijn
van Iterson, Maarten
van Dijk, Freerk
van Galen, Michiel
Bot, Jan
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Article
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taverne
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.
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Taverne, Journal Article
Citation
Bonder, M J, Luijk, R, Zhernakova, D V, Moed, M, Deelen, P, Vermaat, M, van Iterson, M, van Dijk, F, van Galen, M, Bot, J, Slieker, R C, Jhamai, P M, Verbiest, M, Suchiman, H E D, Verkerk, M, van der Breggen, R, van Rooij, J, Lakenberg, N, Arindrarto, W, Kielbasa, S M, Jonkers, I, van 't Hof, P, Nooren, I, Beekman, M, Deelen, J, van Heemst, D, Zhernakova, A, Tigchelaar, E F, Swertz, M A, Hofman, A, Uitterlinden, A G, Pool, R, van Dongen, J, Hottenga, J J, Stehouwer, C D A, van der Kallen, C J H, Schalkwijk, C G, van den Berg, L H, van Zwet, E W, Mei, H, Li, Y, Lemire, M, Hudson, T J, Slagboom, P E, Wijmenga, C, Veldink, J H, van Greevenbroek, M M J, van Duijn, C M, Boomsma, D I, Isaacs, A & BIOS Consortium 2017, 'Disease variants alter transcription factor levels and methylation of their binding sites', Nature Genetics, vol. 49, no. 1, pp. 131–138. https://doi.org/10.1038/ng.3721