Contribution of genetic variation to transgenerational inheritance of DNA methylation

Abstract

Background: Despite the important role DNA methylation plays in transcriptional regulation, the transgenerational inheritance of DNA methylation is not well understood. The genetic heritability of DNA methylation has been estimated using twin pairs, although concern has been expressed whether the underlying assumption of equal common environmental effects are applicable due to intrauterine differences between monozygotic and dizygotic twins. We estimate the heritability of DNA methylation on peripheral blood leukocytes using Illumina HumanMethylation450 array using a family based sample of 614 people from 117 families, allowing comparison both within and across generations.

Results: The correlations from the various available relative pairs indicate that on average the similarity in DNA methylation between relatives is predominantly due to genetic effects with any common environmental or zygotic effects being limited. The average heritability of DNA methylation measured at probes with no known SNPs is estimated as 0.187. The ten most heritable methylation probes were investigated with a genome-wide association study, all showing highly statistically significant cis mQTLs. Further investigation of one of these cis mQTL, found in the MHC region of chromosome 6, showed the most significantly associated SNP was also associated with over 200 other DNA methylation probes in this region and the gene expression level of 9 genes.

Conclusions: The majority of transgenerational similarity in DNA methylation is attributable to genetic effects, and approximately 20% of individual differences in DNA methylation in the population are caused by DNA sequence variation that is not located within CpG sites.

Figure 1

Distribution of heritability estimates for DNA methylation levels. The average genetic heritability estimate is 0.199. A zero estimate for genetic heritability was observed in 17.1% of cases indicating that genetic heritability results in transgenerational inheritance of DNA methylation for at least 65.8% of probes.

Figure 2

Distribution of genetic heritability estimates across the genome. The MHC region, which had the highest estimates of genetic heritability is clearly visible on chromosome 6. Telomeric regions show an increased density of probes with high genetic heritability, although this is primarily due to higher numbers of probes in these regions.

Figure 3

Manhattan plot of the genome-wide association P values for methylation probe cg15671450. The genome-wide significance level of 5 × 10^-8 is indicated by the horizontal line. A highly significant effect is observed cis to the methylation probe on chromosome 6.

Figure 4

Association between rs111482415 and DNA methylation probes in the surrounding 8 Mbp window. The effect size measures the change in the log-odds of the probe being methylated with changing genotype, with positive values indicating an increased average methylation level. Probes with a significant association to rs111482415 at a genome-wide Bonferroni corrected 0.05 level are coloured red. The position of rs111482415 is indicated with a dashed line. See also Additional file 9: Figure S8 and Additional file 8: Table S2.