DNA methylation patterns associate with genetic and gene expression variation in HapMap cell lines

Association analyses of methylation levels with more than three million common single nucleotide polymorphisms (SNPs) identified 180 CpG-sites in 173 genes that were associated with nearby SNPs (putatively in cis, usually within 5 kb) at a false discovery rate of 10%. The most intriguing trans signal was obtained for SNP rs10876043 in the disco-interacting protein 2 homolog B gene (DIP2B, previously postulated to play a role in DNA methylation), that had a genome-wide significant association with the first principal component of patterns of methylation; however, we found only modest signal of trans-acting associations overall. As expected, we found significant negative correlations between promoter methylation and gene expression levels measured by RNA-sequencing across genes. Finally, there was a significant overlap of SNPs that were associated with both methylation and gene expression levels.Our results demonstrate a strong genetic component to inter-individual variation in DNA methylation profiles. Furthermore, there was an enrichment of SNPs that affect both methylation and gene expression, providing evidence for shared mechanisms in a fraction of genes.DNA methylation plays an important regulatory role in eukaryotic genomes. Alterations in methylation can affect transcription and phenotypic variation [1], but the source of variation in DNA methylation itself remains poorly understood. Substantial evidence of inter-individual variation in DNA methylation exists with age [2,3], tissue [4,5], and species [6]. In mammals, DNA methylation is mediated by DNA methyltransferases (DNMTs) that are responsible for de novo methylation and maintenance of methylation patterns during replication. Genes involved in the synthesis of methylation and in DNA demethylation can also affect methylation variation. For example, mutations in DNMT3L [7] and MTHFR [8] associate with global DNA hypo-methylation in human blood. These changes occur at a genome-wide level and are distinct fro