Systematic identification of genetic influences on methylation across the human life course

Abstract

Background: The influence of genetic variation on complex diseases is potentially mediated through a range of highly dynamic epigenetic processes exhibiting temporal variation during development and later life. Here we present a catalogue of the genetic influences on DNA methylation (methylation quantitative trait loci (mQTL)) at five different life stages in human blood: children at birth, childhood, adolescence and their mothers during pregnancy and middle age.

Results: We show that genetic effects on methylation are highly stable across the life course and that developmental change in the genetic contribution to variation in methylation occurs primarily through increases in environmental or stochastic effects. Though we map a large proportion of the cis-acting genetic variation, a much larger component of genetic effects influencing methylation are acting in trans. However, only 7 % of discovered mQTL are trans-effects, suggesting that the trans component is highly polygenic. Finally, we estimate the contribution of mQTL to variation in complex traits and infer that methylation may have a causal role consistent with an infinitesimal model in which many methylation sites each have a small influence, amounting to a large overall contribution.

Conclusions: DNA methylation contains a significant heritable component that remains consistent across the lifespan. Our results suggest that the genetic component of methylation may have a causal role in complex traits. The database of mQTL presented here provide a rich resource for those interested in investigating the role of methylation in disease.

Keywords: Cohort; DNA methylation; Genetic association; Methylation quantitative trait loci; mQTL.

Fig. 1

Temporal pattern of mQTL. a The total number of cis and trans mQTL discovered at each time point. b Total bars represent the SNP heritability at each time point. Each bar is split into genetic variation due to common SNPs acting in cis (blue) and trans (green). Cis and trans variation is further divided into the proportion that is explained by mapped SNPs (p < 1 × 10⁻¹⁴). c The proportion of discovered mQTL at a specific time point that replicate at p < 1 × 10⁻⁷ in each of the other time points. Darker colours correspond to lower replication rates

Fig. 2

Genomic distribution of mQTL. a Distribution of mQTL across genomic features; b distribution of mQTL-associated CpG sites across CpG islands; c distribution of mQTL-associated CpG sites across genic features. d Circos plot illustrating trans mQTL at birth (see Additional file 1: Figure S5 for other time points). From the outside: chromosomes, −log₁₀(p value) for association (red points), density of mQTL (blue bars), density of associated CpGs (green bars), density of genes (gray bars), trans associations between SNP and CpG (lines). e Average estimated cis (top) and trans (bottom) SNP heritability for methylation levels at different genomic features. Bar heights show mean heritability for each genomic feature. Error bars show standard error of the mean heritability. Horizontal lines indicate the mean heritability across all features. UTR untranslated region

Fig. 3

mQTL enrichment in diseases and traits. a Contribution of mQTL identified at each time point to variance of WTCCC common diseases bipolar disorder (BD), coronary artery disease (CAD), Crohns disease (CD), hypertension (HT), rheumatoid arthritis (RA), type 1 diabetes (T1D) and type 2 diabetes (T2D). Red dots represent the component of a trait’s genetic variance attributable to cis-acting mQTL SNPs with significance levels of p < 1 × 10⁻¹⁴, on the liability scale, excluding chromosome 6. Black points depict the point estimates of SNP heritability estimates under the null hypotheses of SNPs coming from genic regions (left plot) or SNPs with the same proportion of genic features as the mQTLs (right plot). P values relate to the proportion of the null estimates that surpass the mQTL estimates. b Enrichment analysis of cis-acting mQTL SNPs with significance levels of p < 1 × 10⁻¹⁴ in large-scale GWAS summary statistics for 33 complex traits. The solid horizontal line denotes empirical p value of 0.05 and the dotted line shows the threshold after correcting for multiple testing. Red bars are based on a null of genic SNPs, blue bars on a null of mQTL-matched SNPs. HDL = high-density lipoprotein cholesterol, LDL = low-density lipoprotein cholesterol, BMD = bone mineral density, FN = femoral neck, LS = lumbar spine, BMI = body mass index, AMD = age-related macular degeneration and ALS = amyotrophic lateral sclerosis