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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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C21orf56 gene region. (a), (b), (c) Genotype at rs8133082 is associated with methylation (cg07747299) and gene expression at C21orf56, plotted per individual colored according to genotype at rs8133082 (GG = black, GT = green, TT = red) for directly genotyped (circles) and imputed (triangles) data. (d) Gene expression levels at C21orf56 after regressing out methylation. (e) Gene expression at C21orf56 (+/-2 kb) genomic region on chromosome 21. Distance is measured on the reverse strand relative to C21orf56 TSS at 46,428,697 bp. Barplots show average gene expression reads per million in the subsets of individuals from each of the three rs8133082-genotype classes. Middle panel shows histone-modification peaks in the region from Encode LCL GM12878. Bottom panel shows the gene-structure of C21orf56, where exons are in bold and the gene is expressed from the reverse strand. Green points indicate the location of four HapMap SNPs (rs8133205, rs6518275, rs8133082, and rs8134519) associated at FDR of 10% with both methylation and gene expression, and Figure S11 in Additional file 1 shows association results for this region with SNPs from the 1,000 Genomes Project. (f) Bisulphite-sequencing results for eight rs8133082-homozygote individuals (4 GG black, 4 TT red) validates the genome-wide methylation assay at cg07747299 and shows the extent of methylation in the surrounding 411 bp region.
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Figure 5: C21orf56 gene region. (a), (b), (c) Genotype at rs8133082 is associated with methylation (cg07747299) and gene expression at C21orf56, plotted per individual colored according to genotype at rs8133082 (GG = black, GT = green, TT = red) for directly genotyped (circles) and imputed (triangles) data. (d) Gene expression levels at C21orf56 after regressing out methylation. (e) Gene expression at C21orf56 (+/-2 kb) genomic region on chromosome 21. Distance is measured on the reverse strand relative to C21orf56 TSS at 46,428,697 bp. Barplots show average gene expression reads per million in the subsets of individuals from each of the three rs8133082-genotype classes. Middle panel shows histone-modification peaks in the region from Encode LCL GM12878. Bottom panel shows the gene-structure of C21orf56, where exons are in bold and the gene is expressed from the reverse strand. Green points indicate the location of four HapMap SNPs (rs8133205, rs6518275, rs8133082, and rs8134519) associated at FDR of 10% with both methylation and gene expression, and Figure S11 in Additional file 1 shows association results for this region with SNPs from the 1,000 Genomes Project. (f) Bisulphite-sequencing results for eight rs8133082-homozygote individuals (4 GG black, 4 TT red) validates the genome-wide methylation assay at cg07747299 and shows the extent of methylation in the surrounding 411 bp region.

Mentions: One example of a SNP, rs8133082, that is both a meQTL and eQTL for the gene C21orf56 is illustrated in Figure 5. When we regress out methylation, this completely removes the association of this SNP with gene expression (Figure 5a, b, c, d). We validated the methylation assay findings at C21orf56 by bisulfite sequencing the methylation probe region in eight samples in our study, four from each homozygote genotype class for the SNP (Figure 5f). The two methylation probes at C21orf56 both had cis meQTLs and overlapped the likely promoter region as indicated by histone modification data (Figure 5e), suggesting that genetic variation may affect the chromatin structure in this region. C21orf56 appears to modulate the response of human LCLs to alkylating agents, and may act as a genomic predictor for inter-individual differences in response to DNA damaging agents [46].


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)

C21orf56 gene region. (a), (b), (c) Genotype at rs8133082 is associated with methylation (cg07747299) and gene expression at C21orf56, plotted per individual colored according to genotype at rs8133082 (GG = black, GT = green, TT = red) for directly genotyped (circles) and imputed (triangles) data. (d) Gene expression levels at C21orf56 after regressing out methylation. (e) Gene expression at C21orf56 (+/-2 kb) genomic region on chromosome 21. Distance is measured on the reverse strand relative to C21orf56 TSS at 46,428,697 bp. Barplots show average gene expression reads per million in the subsets of individuals from each of the three rs8133082-genotype classes. Middle panel shows histone-modification peaks in the region from Encode LCL GM12878. Bottom panel shows the gene-structure of C21orf56, where exons are in bold and the gene is expressed from the reverse strand. Green points indicate the location of four HapMap SNPs (rs8133205, rs6518275, rs8133082, and rs8134519) associated at FDR of 10% with both methylation and gene expression, and Figure S11 in Additional file 1 shows association results for this region with SNPs from the 1,000 Genomes Project. (f) Bisulphite-sequencing results for eight rs8133082-homozygote individuals (4 GG black, 4 TT red) validates the genome-wide methylation assay at cg07747299 and shows the extent of methylation in the surrounding 411 bp region.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3091299&req=5

Figure 5: C21orf56 gene region. (a), (b), (c) Genotype at rs8133082 is associated with methylation (cg07747299) and gene expression at C21orf56, plotted per individual colored according to genotype at rs8133082 (GG = black, GT = green, TT = red) for directly genotyped (circles) and imputed (triangles) data. (d) Gene expression levels at C21orf56 after regressing out methylation. (e) Gene expression at C21orf56 (+/-2 kb) genomic region on chromosome 21. Distance is measured on the reverse strand relative to C21orf56 TSS at 46,428,697 bp. Barplots show average gene expression reads per million in the subsets of individuals from each of the three rs8133082-genotype classes. Middle panel shows histone-modification peaks in the region from Encode LCL GM12878. Bottom panel shows the gene-structure of C21orf56, where exons are in bold and the gene is expressed from the reverse strand. Green points indicate the location of four HapMap SNPs (rs8133205, rs6518275, rs8133082, and rs8134519) associated at FDR of 10% with both methylation and gene expression, and Figure S11 in Additional file 1 shows association results for this region with SNPs from the 1,000 Genomes Project. (f) Bisulphite-sequencing results for eight rs8133082-homozygote individuals (4 GG black, 4 TT red) validates the genome-wide methylation assay at cg07747299 and shows the extent of methylation in the surrounding 411 bp region.
Mentions: One example of a SNP, rs8133082, that is both a meQTL and eQTL for the gene C21orf56 is illustrated in Figure 5. When we regress out methylation, this completely removes the association of this SNP with gene expression (Figure 5a, b, c, d). We validated the methylation assay findings at C21orf56 by bisulfite sequencing the methylation probe region in eight samples in our study, four from each homozygote genotype class for the SNP (Figure 5f). The two methylation probes at C21orf56 both had cis meQTLs and overlapped the likely promoter region as indicated by histone modification data (Figure 5e), suggesting that genetic variation may affect the chromatin structure in this region. C21orf56 appears to modulate the response of human LCLs to alkylating agents, and may act as a genomic predictor for inter-individual differences in response to DNA damaging agents [46].

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