F7. EPIGENOMIC EMBEDDING OF CHILDHOOD ADVERSITY LINKS TO DISEASE RISK AND CHRONIC IMMUNE CHANGES

Background Childhood adversity (CA) is a major risk factor for diverse psychiatric and physical disorders and likely interacts with genetic variation to influence disease vulnerability (gene × environment interplay (G × E)). DNA methylation (DNAm) constitutes a possible mediator, particularly within the immune system, which is implicated in the long-term health consequences of CA. We focus on mapping the epigenetic embedding of CA in the context of genetic variation. Methods We tested for contextual methylation quantitative trait loci (contmeQTLs) in peripheral blood using linear regression models with DNAm as outcome and the interaction of CA and single nucleotide polymorphisms (SNPs) as predictor, combining 3,471 adolescents and adults across six cohorts in a random-effects meta-analysis with replication in three childhood cohorts (N=780). Identified SNPs and CpG-sites were annotated for functionality and disease association. Possible causal involvement in complex traits was tested using Mendelian randomization (MR). We created a polygenic interaction risk score (PIRS) based on DNAm reactivity upon exposure to CA. To understand why these seemingly maladaptive alleles persist in humans, we examined selective pressures on contmeQTLs using > 15,000 ancient genomes from the Allen Ancient DNA Resource. We compared allele frequency trajectories of human-derived contmeQTLs (those arising after the human-chimp split) against ancestral alleles (those present in the human-chimp ancestor), coupled with survival analysis of allele persistence. Results We identified 5,120 contmeQTLs, 99% acting in cis, with 20% replicated in the childhood cohorts. SNPs and CpGs within contmeQTLs showed enrichment in pathways implicated in the major histocompatibility complex and were linked to psychiatric and physical disorders in genome-wide and MR-studies, as well as to psychiatric disorders-associated differential DNAm in post-mortem brain tissue. Using UK Biobank data, in CA-exposed individuals only, the PIRS derived from contmeQTLs was associated with a pro-inflammatory plasma profile which predicted greater disease burden. Human-derived contmeQTLs show signatures of recent positive selection and a higher PIRS predicted later age at death in ancient humans, indicating a survival advantage. Genome-wide association studies have linked these variants to higher cognitive performance alongside increased risk for psychosis and substance use. Discussion This study highlights the relevance of G × E in the epigenetic embedding of CA and demonstrates that epigenetic signatures associated with G × CA are linked to altered immune function. The moderating genetic variants are enriched for SNPs which have been associated with various CA-associated diseases supporting this epigenetic embedding as one common pathway from early exposure to later-in-life disease. Evolutionary genetics suggest contmeQTLs were beneficial in ancient humans, possibly reflecting a trade-off where these genetic variants increase cognition and learning at the cost of psychiatric risk.