Abstract
Backgroundparent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist.Methodsin order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as ‘predicted mRNA expression levels’ of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315).Findingsa set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, ‘lifetime smoking status’ and ‘predicted mRNA expression levels’ of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs.Interpretationthe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases.FundingNSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH.
Highlights
Research in contextEvidence before this studyPrevious population studies showed that parent-origin-effects (POE) on human methylome can be widespread and affect health-related traits and diseases
By systematically screening 101 genetic and environmental factors in a large cohort(GS:SFHS) we provided population-level replicated evidence that those measuring lifestyle and predicted expression of DNA methylation- or imprintingmachinery genes are amongst the factors that can modulate the parent-of-origin effects (POE) of mQTLs for a set of CpG sites
Based on the 2372 previously identified independent mQTL-CpGs pairs containing mQTLs with parent-of-origin effect (1895 independent mQTLs; 381211 SNPs in total) and their regulated CpGs (399 independent CpGs; 586 CpGs in total) [4], we proposed an interaction model which tests for significant interaction effects (Figure 1) between each of the 101 candidate environmental/genetic modifiers available in GS:SFHS and the parent-of-origin effect of each mQTL on the corresponding targeted CpG
Summary
Previous population studies showed that parent-origin-effects (POE) on human methylome can be widespread and affect health-related traits and diseases. Whether the POE remain stable throughout the life or can be modified by genetic or environmental factors was largely unknown. The POE are mainly introduced by imprinting. A case study reported one imprinted locus where the imprinting status was modified by genetic variants and environmental factors such as maternal nutrition and maternal age, and that the modulated imprinting status influenced childhood BMI. Whether the POE at DNA methylation levels could be modified and which genetic/environmental factor could introduce this POE-specific modification effect remained unknown.
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