Genetics and environment distinctively shape the human immune cell epigenome

The epigenome of human immune cells is shaped by both genetics and environmental factors, yet the relative contributions of these influences remain incompletely characterized. Here we use single-nucleus methylation sequencing and assay for transposase-accessible chromatin using sequencing (ATAC–seq) to systematically explore how pathogen and chemical exposures, along with genetic variation, are associated with changes in the immune cell epigenome. Distinct exposure-associated differentially methylated regions (eDMRs) and differentially accessible regions were identified, and a significant correlation between these two modalities was observed. Additionally, genotype-associated DMRs (gDMRs) were detected, indicating that eDMRs are enriched in regulatory regions, whereas gDMRs are preferentially located within gene body marks. Disease-associated single-nucleotide polymorphisms were frequently colocalized with methylation quantitative trait loci, providing cell-type-specific insights into the genetic basis of diseases. These findings highlight the complex interplay between genetic and environmental factors in shaping the immune cell epigenome and advance understanding of immune cell regulation in health and disease.