Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome

Abstract

Backgroundparent-of-origin effects (POE) play important roles in development and complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies have 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 these 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 early/late lifestyle/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). Resultsa 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. Importantly, the POE on one of the CpGs were modified by both genetic and environmental factors. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. Conclusionsthe 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. Key MessagesO_LIPrevious population studies showed that parent-origin-effects(POE) on human methylome can be widespread and affect health-related traits and diseases. C_LIO_LIWhether the POE remained stable throughout the life or can be modified by genetic or environmental factors were largely unknown. C_LIO_LIBy systematically screening 101 genetic and environmental factors in a large cohort(GS:SFHS) we provided the first population-level replicated evidence that those measuring lifestyle (smoking) and predicted expression of DNA methylation- or imprinting-machinery genes are amongst the factors that can modulate the POE of mQTLs for a set of CpG sites. C_LIO_LIWe found those modifiable-POE-regulated CpGs are also phenotypically relevant - one is associated with the plasma levels of CLEC4C and health-related phenotypes such as HDL levels. C_LIO_LIThe modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation and their potential phenotypic consequences. This also provided a paradigm for further studies to explore how environmental and genetic effects can be integrated at methylation level. C_LI