期刊
NATURE GENETICS
卷 49, 期 1, 页码 131-138出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3721
关键词
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资金
- BBMRI-NL
- Dutch government [NWO 184.021.007]
- Dutch Research Council [ZonMW-VIDI 917.14.374]
- ERC Starting Grant [637640]
- FP7 [259867]
- SURF Cooperative
- European Research Council (ERC) [637640] Funding Source: European Research Council (ERC)
Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences(1,2). 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(3,4). The analysis of DNA methylation, a key component of the epigenome(5,6), offers highly complementary data on the regulatory potential of genomic regions(7,8). 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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