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

TL;DR

This study uses monozygotic twins to find genetic variants that influence DNA methylation variability, revealing gene-environment interactions and cell-type effects.

Contribution

The study identifies vmeQTLs in twins, showing how genetic variants interact with environment and cell types to affect DNA methylation.

Findings

Over a third of vmeQTLs show consistent gene-environment interactions across twin datasets.

Most vmeQTLs replicate in non-twin adults and show longitudinal stability.

vmeQTLs interacting with blood cell types are linked to immune disease susceptibility.

Abstract

Genetic 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.

We optimize the value of monozygotic twin studies to identify and replicate vmeQTLs for blood DNA methylation variance at 358 CpGs in 988 adult monozygotic twin pairs from two European twin registries. Over a third of vmeQTLs capture identical vmeQTL-environmental factor interactions in both datasets, and the majority of interactions are observed with blood cell counts. Correspondingly, over 60% of CpGs affected by genotype-monocyte and genotype-T cell interactions replicate as CpGs affected by genetic effects in the relevant cell type in an independent dataset. Most vmeQTLs also replicate in 1,348 UK non-twin adults and show longitudinal stability in a sample subset. Integrating gene expression and phenotype association results identifies 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.

Our findings identify novel genetic effects on human DNA methylation variability within a unique monozygotic twin study design. The results show the potential of vmeQTLs to identify gene-environment interactions and provide novel insights into complex traits.

The online version contains supplementary material available at 10.1186/s13059-026-03947-w.

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