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

Jordana T Bell,Daniel J Gaffney,Yoav Gilad,Roger Pique-Regi,Joseph K Pickrell,Jacob F Degner,Jonathan K Pritchard,Athma A Pai

doi:10.1186/gb-2011-12-1-r10

Abstract

BackgroundDNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles. Here we measured methylation levels at 22,290 CpG dinucleotides in lymphoblastoid cell lines from 77 HapMap Yoruba individuals, for which genome-wide gene expression and genotype data were also available.ResultsAssociation 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.ConclusionsOur 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.

Highlights

DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles
We tested for correlations with potential confounding variables that could affect methylation levels in lymphoblastoid cell line (LCL) [29], such as LCL cell growth rate, copy numbers of Epstein-Barr virus, and other measures of biological variation that were available for 60 of the individuals in our study [30]; these did not significantly explain variation in the methylation levels in our sample (Figure S1 in Additional file 1)
We observed an influence of HapMap Phase on the distribution of the first principal component loadings in the autosomal data, suggesting that the first methylation principal component may in part capture technical variation potentially related to LCL culture

Summary

Introduction

DNA methylation is an essential epigenetic mechanism involved in gene regulation and disease, but little is known about the mechanisms underlying inter-individual variation in methylation profiles. Genes involved in the synthesis of methylation and in DNA demethylation can affect methylation variation. Mutations in DNMT3L [7] and MTHFR [8] associate with global DNA hypo-methylation in human blood. These changes occur at a genomewide level and are distinct from genetic variants that impact DNA methylation variability in targeted genomic regions, for example, genetic polymorphisms associated with differential methylation in the H19/IGF2 locus [9]

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Discussion

Conclusion