Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation

Lucas T Husquin,Lisa M Mcewen,Michael S Kobor,Hugues Aschard,Lluis Quintana-Murci,Julia L Macisaac,Maxime Rotival,Hélène Quach,Maud Fagny,Nora Zidane,Etienne Patin

doi:10.1186/s13059-018-1601-3

Abstract

BackgroundDNA 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, their genetic determinants, and their respective causal impact on immune gene regulation remain elusive.ResultsWe report extensive population differences in DNA methylation between 156 individuals of African and European descent, detected in primary monocytes that are used as a model of a major innate immunity cell type. Most of these differences (~ 70%) are driven by DNA sequence variants nearby CpG sites, 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 variation in DNA methylation is associated with varying gene expression levels following 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.ConclusionUsing 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.

Highlights

DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases
Population differences in DNA methylation profiles of primary monocytes To assess population differences in DNA methylation of a purified innate immune cell type, we characterized DNA methylation variation at > 850,000 CpG sites across the genome, in monocytes originating from 156 male healthy volunteers: 78 of African descent (AFB, median age = 30.9 years) and 78 of European descent (EUB, median age = 25.9 years), all living in Belgium
At a false discovery rate (FDR) = 1%, we identified 77,857 sites (14.1% of the total number) that presented a significant difference between AFB and EUB in their mean level of DNA methylation, after adjusting for age and surrogate variables

Summary

Introduction

DNA methylation is influenced by both environmental and genetic factors and is increasingly thought to affect variation in complex traits and diseases. Individuals and populations display variable susceptibility to infectious diseases, chronic inflammatory disorders, and autoimmunity [1, 2]. As the immune system is the primary interface with the human pathogenic environment, the study of DNA methylation [12, 13] offers a unique opportunity to explore the interplay between the genome and environmental cues. DNA methylation variation has been associated with complex traits, including aging [31], body mass index [32], various cancers [33, 34], obesity [35], and autoimmune and inflammatory disorders [36, 37]. Most studies of human epigenome variation, both in health and disease conditions, have focused on populations of homogeneous genetic ancestry, primarily of European descent

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