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.
Highlights
The second stage applied a Parent-of-origin effects (POE)–methylation quantitative trait loci (mQTL) analysis that accounted for POE to localise the SNPs that introduce the POE on the identified CpGs displaying POE (CpG) candidates from the first stage
Using a variance component method, we identified 733 independent CpGs (984 total), of which 331 were previously unidentified, where methylation levels displayed an increased full-sibling and/or oneparent–offspring methylation level similarity relative to expectations under additive inheritance patterns, suggesting putative POEs caused by imprinting
For 399 independent CpGs (171 previously unidentified), we identified genetic variants (POE–mQTLs) that regulate the CpGs through POEs
Summary
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. POEs in these regions can be explicitly modelled in association tests between SNPs and methylation levels for each CpG, assuming allelic effects differ between maternally and paternally inherited alleles[13,14] Whereas this approach enables both the identification of imprintingassociated POE in methylation levels and the localisation of the SNPs associated with that POE, the limitation lies in the huge multiple testing burden introduced by the number of SNP–CpG pairwise tests for a genome-wide scan. Further methodological advances are required in order to improve understanding of the role of POEs in the genetic control of methylation levels and potentially better explain the influence of POEs on phenotypic variation
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