Disease variants alter transcription factor levels and methylation of their binding sites
Bonder MJ., Luijk R., Zhernakova D., Moed M., Deelen P., Vermaat M., van Iterson M., van Dijk F., van Galen M., Bot J., Slieker R., Jhamai M., Verbiest M., Suchiman E., Verkerk M., van der Breggen R., van Rooij J., Lakenberg N., Arindrarto W., Kielbasa S., Jonkers I., van t Hof P., Nooren I., Beekman M., Deelen J., van Heemst D., Zhernakova A., Tigchelaar E., Swertz M., Hofman A., Uitterlinden A., Pool R., van Dongen J., Hottenga J., Stehouwer CDA., van der Kallen CJH., Schalkwijk C., van den Berg L., van Zwet E., Mei H., Li Y., Lemire M., Hudson T., Slagboom E., Wijmenga C., Veldink J., van Greevenbroek MMJ., van Duijn C., Boomsma D., Isaacs A., Jansen R., van Meurs J., t Hoen PAC., Franke L., Heijmans B.
Most disease associated genetic risk factors are non-coding, 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 downstream effects of disease variants but the large majority remains unexplained.. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. However, a large-scale, combined analysis of methylome and transcriptome data to infer downstream effects of disease variants is lacking. Here, we show that disease variants have wide-spread effects on DNA methylation in trans that likely reflect the downstream effects on binding sites of cis-regulated transcription factors. Using data on 3,841 Dutch samples, we detected 272,037 independent cis-meQTLs (FDR < 0.05) and identified 1,907 trait-associated SNPs that affect methylation levels of 10,141 different CpG sites in trans (FDR < 0.05), an eight-fold increase in the number of downstream effects that was known from trans-eQTL studies. Trans-meQTL CpG sites are enriched for active regulatory regions, being correlated with gene expression and overlap with Hi-C determined interchromosomal contacts. We detected many trans-meQTL SNPs that affect expression levels of nearby transcription factors (including NFKB1, CTCF and NKX2-3), while the corresponding trans-meQTL CpG sites frequently coincide with its respective binding site. Trans-meQTL mapping therefore provides a strategy for identifying and better understanding downstream functional effects of many disease-associated variants.