Disease variants alter transcription factor levels and methylation of their binding sites.
Bonder MJ., Luijk R., Zhernakova DV., Moed M., Deelen P., Vermaat M., van Iterson M., van Dijk F., van Galen M., Bot J., Slieker RC., Jhamai PM., Verbiest M., Suchiman HED., Verkerk M., van der Breggen R., van Rooij J., Lakenberg N., Arindrarto W., Kielbasa SM., Jonkers I., van 't Hof P., Nooren I., Beekman M., Deelen J., van Heemst D., Zhernakova A., Tigchelaar EF., Swertz MA., Hofman A., Uitterlinden AG., Pool R., van Dongen J., Hottenga JJ., Stehouwer CDA., van der Kallen CJH., Schalkwijk CG., van den Berg LH., van Zwet EW., Mei H., Li Y., Lemire M., Hudson TJ., BIOS Consortium None., Slagboom PE., Wijmenga C., Veldink JH., van Greevenbroek MMJ., van Duijn CM., Boomsma DI., Isaacs A., Jansen R., van Meurs JBJ., 't Hoen PAC., Franke L., Heijmans BT.
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.