| Literature DB >> 27918535 |
Marc Jan Bonder1, René Luijk2, Daria V Zhernakova1, Matthijs Moed2, Patrick Deelen1,3, Martijn Vermaat4, Maarten van Iterson2, Freerk van Dijk1,3, Michiel van Galen3, Jan Bot5, Roderick C Slieker2, P Mila Jhamai6, Michael Verbiest3, H Eka D Suchiman2, Marijn Verkerk6, Ruud van der Breggen2, Jeroen van Rooij6, Nico Lakenberg2, Wibowo Arindrarto7, Szymon M Kielbasa8, Iris Jonkers1, Peter van 't Hof8, Irene Nooren5, Marian Beekman2, Joris Deelen2, Diana van Heemst9, Alexandra Zhernakova1, Ettje F Tigchelaar1, Morris A Swertz1,3, Albert Hofman10, André G Uitterlinden6, René Pool11, Jenny van Dongen11, Jouke J Hottenga11, Coen D A Stehouwer12,13, Carla J H van der Kallen12,13, Casper G Schalkwijk12,13, Leonard H van den Berg14, Erik W van Zwet7, Hailiang Mei8, Yang Li1, Mathieu Lemire15, Thomas J Hudson15,16,17, P Eline Slagboom2, Cisca Wijmenga1, Jan H Veldink14, Marleen M J van Greevenbroek12,13, Cornelia M van Duijn18, Dorret I Boomsma11, Aaron Isaacs13,18,19, Rick Jansen20, Joyce B J van Meurs6, Peter A C 't Hoen4, Lude Franke1, Bastiaan T Heijmans2.
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.Entities:
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Year: 2016 PMID： 27918535 DOI： 10.1038/ng.3721
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330