Disease Variants Alter Transcription Factor Levels and Methylation of Their Binding Sites

Nat Genet. 2017 Jan;49(1):131-138. doi: 10.1038/ng.3721. Epub 2016 Dec 5.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cohort Studies
  • DNA Methylation*
  • Disease / genetics*
  • Female
  • Gene Expression Regulation*
  • Genome, Human
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Quantitative Trait Loci*
  • Transcription Factors / metabolism*

Substances

  • Transcription Factors