Genetic impacts on within-pair DNA methylation variance in monozygotic twins capture gene-environment interactions and cell-type effects

Zhang, X.; Yet, I.; Villicana, S.; Castillo-Fernandez, J.; Mangino, M.; Hottenga, J. J.; Tsai, P.-C.; Min, J.; Falchi, M.; Wong, A.; Boomsma, D.; Ong, K.; van Dongen, J.; Bell, J. T.

doi:10.1101/2025.06.17.659865

bioRxiv · 10.1101/2025.06.17.659865

Genetic impacts on within-pair DNA methylation variance in monozygotic twins capture gene-environment interactions and cell-type effects

Zhang, X.·Yet, I.·Villicana, S.·Castillo-Fernandez, J.·Mangino, M.·Hottenga, J. J.·Tsai, P.-C.·Min, J.·Falchi, M.·Wong, A.·Boomsma, D.·Ong, K.·van Dongen, J.·Bell, J. T.

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Abstract

BackgroundGenetic variants that are associated with phenotypic variability, or variance quantitative trait loci (vQTLs), have been detected for multiple human traits. Gene-environment interactions can lead to differential phenotypic variability across genotype groups, therefore, genetic variants that interact with environmental exposures can manifest as vQTLs. Although changes in DNA methylation variability have been observed in several diseases, vQTLs for methylation levels (vmeQTL) have not yet been explored in depth. ResultsWe optimize the value of monozygotic (MZ) twin studies to identify and replicate vmeQTLs for blood DNA methylation variance at 358 CpGs in 988 adult MZ twin pairs from two European twin registries. Over a third of vmeQTLs captured identical vmeQTL-environmental factor interactions in both datasets, and the majority of interactions were observed with blood cell counts. Correspondingly, over 60% of CpGs affected by genotype-monocyte and genotype-T cell interactions replicated as CpGs affected by genetic effects in the relevant cell type in an independent dataset. Most vmeQTLs also replicated in 1,348 UK non-twin adults and showed longitudinal stability in a sample subset. Integrating gene expression and phenotype association results identified multiple vmeQTLs that capture GxE effects relevant to human health. Examples include vmeQTLs interacting with blood cell type to influence DNA methylation in FAM65A, NAPRT, and CSGALNACT1 underlying immune disease susceptibility and progression. ConclusionOur findings identify novel genetic effects on human DNA methylation variability within a unique MZ twin study design. The results show the potential of vmeQTLs to identify gene-environment interactions and provide novel insights into complex traits.

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Zhang, X., Yet, I., Villicana, S., Castillo-Fernandez, J., Mangino, M., Hottenga, J. J., Tsai, P.-C., Min, J., Falchi, M., Wong, A., Boomsma, D., Ong, K., van Dongen, J., Bell, J. T.. 2025-06-21. Genetic impacts on within-pair DNA methylation variance in monozygotic twins capture gene-environment interactions and cell-type effects. https://doi.org/10.1101/2025.06.17.659865

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