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. 2010 Mar 12;86(3):411-9.
doi: 10.1016/j.ajhg.2010.02.005.

Genetic control of individual differences in gene-specific methylation in human brain

Dandan Zhang  1 , Lijun Cheng, Judith A Badner, Chao Chen, Qi Chen, Wei Luo, David W Craig, Margot Redman, Elliot S Gershon, Chunyu Liu
Affiliations

Genetic control of individual differences in gene-specific methylation in human brain

Dandan Zhang et al. Am J Hum Genet. .

Abstract

We have observed extensive interindividual differences in DNA methylation of 8590 CpG sites of 6229 genes in 153 human adult cerebellum samples, enriched in CpG island "shores" and at further distances from CpG islands. To search for genetic factors that regulate this variation, we performed a genome-wide association study (GWAS) mapping of methylation quantitative trait loci (mQTLs) for the 8590 testable CpG sites. cis association refers to correlation of methylation with SNPs within 1 Mb of a CpG site. 736 CpG sites showed phenotype-wide significant cis association with 2878 SNPs (after permutation correction for all tested markers and methylation phenotypes). In trans analysis of methylation, which tests for distant regulation effects, associations of 12 CpG sites and 38 SNPs remained significant after phenotype-wide correction. To examine the functional effects of mQTLs, we analyzed 85 genes that were with genetically regulated methylation we observed and for which we had quality gene expression data. Ten genes showed SNP-methylation-expression three-way associations-the same SNP simultaneously showed significant association with both DNA methylation and gene expression, while DNA methylation was significantly correlated with gene expression. Thus, we demonstrated that DNA methylation is frequently a heritable continuous quantitatively variable trait in human brain. Unlike allele-specific methylation, genetic polymorphisms mark both cis- and trans-regulatory genetic sites at measurable distances from their CpG sites. Some of the genetically regulated DNA methylation is directly connected with genetically regulated gene expression variation.

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Figures

Figure 1
Figure 1
p Values and Distances between CpG Sites and SNPs cis SNPs are plotted by their relative distance from CpG sites on the horizontal axis and genotype-methylation association p values on the vertical axis. The y axis is -log10 transformed permutation p values of associations between cis SNPs and DNA methylation (109 permutations). Red dots represent phenotype-wide significant cis associations and green triangles mean region-wide significance. The box plot shows the summary statistics of distance at x axis. For the box plot, the right end is the lowest point within 1.5 interquartile (distance between third and first quartile) from the lower quartile, and the left end is the highest point within 1.5 interquartile of the upper quartile, the top of the box is the upper or third quartile, the bottom of the box is lower or first quartile, the middle bar is median value, and the circles are possible outliers. The median value of distance between cis SNPs and CpG sites is 34.38 kb. Plot and box plot were created in R.
Figure 2
Figure 2
Methylation of cg23815491 Measured by Pyrosequencing and Beadchip Associated with SNP rs10492831 DNA methylation of cg23815491 measured by Illumina Beadchip (right) and pyrosequencing (left). DNA methylation was plotted against the genotypes of rs10492813. The x axis has three genotypes of rs10492813, and y axis was the raw data measured DNA methylation by pyrosequening and Illumina Beadchips. Minor allele T of rs10492813 is significantly associated with high methylation level of cg23825491 in a cis manner assessed by Beadchip (Wald p value = 1.02E-46). The same trend was observed in pyrosequencing data (Wald p value = 1.50E-56). The correlation coefficient between the two methods was r = 0.91. For each box plot, the top bar is the lowest point within 1.5 interquartile from the lower quartile, and the left end is the highest point within 1.5 interquartile of the upper quartile, the top of box is the upper or third quartile, the bottom of box is the lower or first quartile, the middle bar is the median value, and circles are possible outliers.
Figure 3
Figure 3
DNA Methylation and Gene Expression of IRF6 Plotted by Genotypes of rs2235375 DNA methylation (left) and gene expression (right) of IRF6 is correlated with genotypes of rs2235375. The x axis has three genotypes of rs2235375, and y axis displays post-SVA+COMBAT residuals representing DNA methylation and gene expression levels. Minor allele C of rs2235375 is significantly associated with high methylation level of IRF6 in a cis manner and simultaneously associated with low gene expression of IRF6.
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