Epigenomic embedding of childhood adversity links to disease risk and chronic inflammation

Childhood adversity (CA) is a major risk factor for diverse psychiatric and physical disorders and is thought to interact with genetic variation to influence disease vulnerability via gene-environment interplay (GxE). DNA methylation (DNAm) may mediate these effects, particularly within the immune system, which is implicated in the long-term health consequences of CA. We mapped the epigenetic embedding of CA in immune cells by testing for contextual methylation quantitative trait loci (contmeQTLs) in peripheral blood using data from 3,471 adolescents and adults across six cohorts, followed by replication in three childhood cohorts (N=780). Meta-analysis identified 5,120 contmeQTLs, > 99% acting in cis, with 20% replicated. These loci were enriched for immune-related pathways, particularly within the major histocompatibility complex, and were linked to psychiatric and physical disorders in (epi)genome-wide association studies, as well as to psychiatric disorders-associated differential DNAm in post-mortem brain tissue. Using UK Biobank data, in CA-exposed individuals only, a polygenic interaction reactivity score derived from contmeQTLs was associated with a pro-inflammatory plasma profile which predicted greater disease burden. Our findings reveal genetic moderation of the epigenetic embedding of CA in immune cells, highlight associated immune and inflammatory alterations, and support this pathway as a potential shared mechanism linking early life adversity to later-life disease.