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

Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK - Genome Biol. (2011)

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. jordana@well.ox.ac.uk

ABSTRACT

Background: 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. 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.

Results: 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.

Conclusions: 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.

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Related in: MedlinePlus

The overlap between meQTLs and eQTLs. (a) QQ-plot describing the eQTL association P-values in 180 cis-meQTL SNPs (red) and in eight samples of SNPs that match the cis-meQTL SNPs for minor allele frequency and distance-to-probe distributions (black). (b) Association signals in 508 FDR 10% eQTLs before and after regressing out gene-specific methylation. In black are 439 eQTLs that overlap across the two phenotypes, in red are 45 eQTLs present before methylation regressions, and in blue are 24 eQTLs present after regressing out methylation. The flat lines (green) correspond to the FDR 10% eQTL threshold.
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Figure 4: The overlap between meQTLs and eQTLs. (a) QQ-plot describing the eQTL association P-values in 180 cis-meQTL SNPs (red) and in eight samples of SNPs that match the cis-meQTL SNPs for minor allele frequency and distance-to-probe distributions (black). (b) Association signals in 508 FDR 10% eQTLs before and after regressing out gene-specific methylation. In black are 439 eQTLs that overlap across the two phenotypes, in red are 45 eQTLs present before methylation regressions, and in blue are 24 eQTLs present after regressing out methylation. The flat lines (green) correspond to the FDR 10% eQTL threshold.

Mentions: Finally, we examined the overlap in regulatory variation that affects both methylation and gene expression levels using RNA-sequencing data [24]. We hypothesized that since DNA methylation can regulate gene expression, then variants that affect methylation should often have consequent effects on gene expression. The first way that we looked at this was to take the set of 180 SNPs that are meQTLs at FDR <10% (taking only the most significant SNP for each meQTL). We then tested each of these SNPs for association with expression levels of nearby genes (Figure 4a, red points). There is a clear enrichment of association with expression levels compared to the hypothesis (black line) and compared to sets of control SNPs that are matched in terms of allele frequency and distance-to-probe distributions (black dots).


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

Bell JT, Pai AA, Pickrell JK, Gaffney DJ, Pique-Regi R, Degner JF, Gilad Y, Pritchard JK - Genome Biol. (2011)

The overlap between meQTLs and eQTLs. (a) QQ-plot describing the eQTL association P-values in 180 cis-meQTL SNPs (red) and in eight samples of SNPs that match the cis-meQTL SNPs for minor allele frequency and distance-to-probe distributions (black). (b) Association signals in 508 FDR 10% eQTLs before and after regressing out gene-specific methylation. In black are 439 eQTLs that overlap across the two phenotypes, in red are 45 eQTLs present before methylation regressions, and in blue are 24 eQTLs present after regressing out methylation. The flat lines (green) correspond to the FDR 10% eQTL threshold.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3091299&req=5

Figure 4: The overlap between meQTLs and eQTLs. (a) QQ-plot describing the eQTL association P-values in 180 cis-meQTL SNPs (red) and in eight samples of SNPs that match the cis-meQTL SNPs for minor allele frequency and distance-to-probe distributions (black). (b) Association signals in 508 FDR 10% eQTLs before and after regressing out gene-specific methylation. In black are 439 eQTLs that overlap across the two phenotypes, in red are 45 eQTLs present before methylation regressions, and in blue are 24 eQTLs present after regressing out methylation. The flat lines (green) correspond to the FDR 10% eQTL threshold.
Mentions: Finally, we examined the overlap in regulatory variation that affects both methylation and gene expression levels using RNA-sequencing data [24]. We hypothesized that since DNA methylation can regulate gene expression, then variants that affect methylation should often have consequent effects on gene expression. The first way that we looked at this was to take the set of 180 SNPs that are meQTLs at FDR <10% (taking only the most significant SNP for each meQTL). We then tested each of these SNPs for association with expression levels of nearby genes (Figure 4a, red points). There is a clear enrichment of association with expression levels compared to the hypothesis (black line) and compared to sets of control SNPs that are matched in terms of allele frequency and distance-to-probe distributions (black dots).

Bottom Line: 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA. jordana@well.ox.ac.uk

ABSTRACT

Background: 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. 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.

Results: 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.

Conclusions: 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.

Show MeSH
Related in: MedlinePlus