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

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.; 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.; van der Kallen, C. J.; Schalkwijk, C. G.; van den Berg, L. H.; van Zwet, E. W.; Mei, H.; Li, Y.; Lemire, M.; Hudson, T. J.; Consortium, Bios; Slagboom, P. E.; Wijmenga, C.; Veldink, J. H.; van Greevenbroek, M. M.; van Duijn, C. M.; Boomsma, D. I.; Isaacs, A.; Jansen, R.; van Meurs, J. B.; t Hoen, P. A.; Franke, L.; Heijmans, B. T.

doi:10.1038/ng.3721

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

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Deelen, J.
Deelen – Genetics and Biomarkers of Human Ageing, Research Groups, Max Planck Institute for Biology of Ageing, Max Planck Society;

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https://www.ncbi.nlm.nih.gov/pubmed/27918535
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Citation

Bonder, M. J., Luijk, R., Zhernakova, D. V., Moed, M., Deelen, P., Vermaat, M., et al. (2016). Disease variants alter transcription factor levels and methylation of their binding sites. Nat Genet, 49(1), 131-138. doi:10.1038/ng.3721.

Cite as: https://hdl.handle.net/21.11116/0000-000B-55E8-0

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.