Parent of origin genetic effects on methylation in humans are common and influence complex trait variation

Abstract

Parent-of-origin effects (POE) exist when there is differential expression of alleles inherited from the two parents. A genome-wide scan for POE on DNA methylation at 639,238 CpGs in 5,101 individuals identifies 733 independent methylation CpGs potentially influenced by POE at a false discovery rate ≤ 0.05 of which 331 had not previously been identified. Cis and trans methylation quantitative trait loci (mQTL) regulate methylation variation through POE at 54% (399/733) of the identified POE-influenced CpGs. The combined results provide strong evidence for previously unidentified POE-influenced CpGs at 171 independent loci. Methylation variation at 14 of the POE-influenced CpGs is associated with multiple metabolic traits. A phenome-wide association analysis using the POE mQTL SNPs identifies a previously unidentified imprinted locus associated with waist circumference. These results provide a high resolution population-level map for POE on DNA methylation sites, their local and distant regulators and potential consequences for complex traits.

Fig. 1

The expected phenotypic covariance structures between nuclear family members introduced by different POE patterns. The bar charts show putative levels of methylation associated with the four possible genotypes at a SNP controlling imprinting (paternal allele in blue, maternal allele in red). The family pedigrees show as shaded the family members between which similarity in methylation is increased due to these patterns of imprinting

Fig. 2

Example of a novel CpG site (cg05875302) influenced by maternal imprinting POE. Upper panel: bars represent estimated variance explained by each component in the selected model for the site displaying significant maternal imprinting (cg05875302, red arrow) and the sites within 20 kb on either side of the selected site. Bottom left panel: regional plot of –log_e (p-value from LRT) of the POE in the selected (red ringed black dot) and surrounding CpG sites with matrix of pairwise correlations of methylation level between these sites in the heatmap below. Bottom right panel: pairwise correlation between methylation M values (corrected for technical and biological covariates) between different pairs of nuclear family members

Fig. 3

Genomic annotations significantly enriched in (red) or depleted of (blue) POE-influenced methylation CpGs. Error bars: 95% confidence interval

Fig. 4

Methylation CpGs regulated by SNP rs231356. SNP rs231356 acts both as a cis-POE–mQTL and a trans-POE–mQTL. Red arrows: location of the CpG in the chromosome. Boxplots show the allelic effects of rs231356 on methylation of three CpG sites (cg09518720, in cis, and cg05884032 and cg23776532, in trans). Boxplots: centre line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers

Fig. 5

CpGs and complex traits regulated by SNP rs6100212. Upper: this SNP was located upstream of gene PIEZO1P2 and overlapped with H3K27ac and CTCF signals. The SNP was also significant for imbalanced methylation (GIT), but not significant in allelic-specific methylation (ASM) or mQTL (classical additive model) analysis as reported by an independent study. Left bottom: the SNP acted as a cis-POE–mQTL for methylation sites causing a complex imprinting pattern (cg26102503 as an example). Middle and right bottom: the SNP was also shown a regulatory role in waist (Phenome-wide significance), BMI, body fat and WHR (per-trait significance), introducing a similar complex imprinting pattern. Boxplots: centre line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers