Genetic Control of Individual Differences in Gene-Specific Methylation in Human Brain

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.

Vitamin D receptor gene methylation is associated with ethnicity, tuberculosis, and TaqI polymorphism

“…Rather than studying genetic variants in isolation, the common disease genetic epigenetic (CDGE) hypothesis encourages the simultaneous analysis of both genetic and epigenetic variants (MVPs) to construct 'hepitypes' in order to increase the power of associations in epidemiological studies and minimise inconsistent associations [18,21]. Analysing both the genetic and epigenetic characteristics of a gene and their interaction in disease has recently been the focus of a number of studies [22][23][24]. Cis interactions between genetic and epigenetic variants involve the direct modulation of CpG methylation by SNPs [18] and the correlation of methylation with SNPs within 1 Mb of a CpG [24] while trans interactions involve regulation effects between CpGs and SNPs from more distant genomic regions, including regions from different chromosomes [24].…”

“…Analysing both the genetic and epigenetic characteristics of a gene and their interaction in disease has recently been the focus of a number of studies [22][23][24]. Cis interactions between genetic and epigenetic variants involve the direct modulation of CpG methylation by SNPs [18] and the correlation of methylation with SNPs within 1 Mb of a CpG [24] while trans interactions involve regulation effects between CpGs and SNPs from more distant genomic regions, including regions from different chromosomes [24].…”

Epigenetics in the Human Brain

“…On the basis of DNA methylation analyses in blood chromatin collected across three generations from the same pedigrees, more than 92% of the differences in methylcytosine load between alleles is explained by haplotype, suggesting a dominant role of genetic variation in the establishment of epigenetic markings, as opposed to environmental influences (Gertz et al, 2011). Likewise, in the human cerebral and cerebellar cortex, methylation of several hundred CpG enriched sequences is significantly affected by genetic variations, including single-nucleotide polymorphisms (SNPs) separated from the CpG site by 41 Mb (Numata et al, 2012;Zhang et al, 2010a). An even larger number of genetic polymorphisms were linked to gene expression differences in the prefrontal cortex, including many SNP-based haplotypes within promoters and around the 5 0 ends of annotated transcripts (Colantuoni et al, 2011).…”

A non-genetic, epigenetic-like mechanism of telomere length inheritance?

“…That is, the information is encoded in the length of the telomeres, not in the repeated TTAGGG sequence. Note that there is indeed an effect of genetic variants on TL, 7 but this also the case for DNAmethylation, 12 simply implying that epigenetic(-like) features are also partially under genetic control. Importantly, together with the telomeres, a stable phenotype is inherited as well, ie, absence of replicative senescence, with associated gene expression pattern.…”