Exploring the Genetic Basis of Human Population Differences in DNA Methylation and their Causal Impact on Immune Gene Regulation

Background: DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Yet, the extent of ancestry-related differences in DNA methylation, its genetic determinants, and their respective causal impact on immune gene regulation remain elusive. Results: We report extensive population differences in DNA methylation between 156 individuals of African and Europeandescent —detected in primary monocytes that were used as a model of a major innate immunity cell type. Most of these differences (~70%) were driven by DNA sequence variants nearby CpG sites (meQTLs), which account for ~60% of the variance in DNA methylation. We also identify several master regulators of DNA methylation variation in trans, including a regulatory hub nearby the transcription factor-encoding CTCF gene, which contributes markedly to ancestry-related differences in DNA methylation. Furthermore, we establish that variationin DNA methylation isassociated with varying gene expression levelsfollowing mostly, but not exclusively, a canonical model of negative associations, particularly in enhancer regions. Specifically, we find that DNA methylation highly correlates with transcriptional activity of 811 and 230 genes, at the basal state and upon immune stimulation, respectively. Finally, using a Bayesian approach, we estimate causal mediation effects of DNA methylation on gene expression in ~20% of the studied cases, indicating that DNA methylation can play an active role in immune gene regulation. Conclusion: Using a system-level approach, our study reveals substantial ancestry-related differences in DNA methylation and provides evidence for their causal impact on immune gene regulation. 156 Samples analyzed, 78 of African descent and 78 of European descent. Replicates are not included