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Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G + CA) and interactive (G × CA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G + CA or G × CA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with G × CA interactions explaining most variance. The consistent G × CA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.

DNA methylation quantitative trait locus (mQTL) analyses on 32,851 participants identify genetic variants associated with DNA methylation at 420,509 sites in blood, resulting in a database of >270,000 independent mQTLs. Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. Here we describe results of DNA methylation-quantitative trait loci (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTL of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We reveal that the genetic architecture of DNAm levels is highly polygenic and DNAm exhibits signatures of negative and positive natural selection. Using shared genetic control between distal DNAm sites we construct networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic factors are associated with both blood DNAm levels and complex diseases but in most cases these associations do not reflect causal relationships from DNAm to trait or vice versa indicating a more complex genotype-phenotype map than has previously been hypothesised.

Background Traumatic experiences during childhood are considered a major risk factor for depression in adulthood. Childhood trauma may induce physiological dysregulation with long-term effects of increased allostatic load until adulthood, which may lead to depression. Thus, our aim was to investigate whether allostatic load – which represents a multi-system measure of physiological dysregulation – mediates the association between childhood trauma and adult depression. Methods The study sample consisted of 324 depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project and 261 mentally healthy control participants. The mediation analysis using a case-control approach included childhood trauma, i.e., physical and sexual abuse, as predictor variables and an allostatic load index comprised of 12 stress-related biomarkers as mediator. Age and sex were included as covariates. Results Mediation analyses revealed that the influence of physical abuse, but not sexual abuse, during childhood on depression in adulthood was mediated by allostatic load. This effect was moderated by age: particularly young (18–42 years) and middle-aged (43–54 years) adults with a history of physical abuse during childhood exhibited high allostatic load, which in turn was associated with increased rates of depression, but this was not the case for older participants (55–81 years). Conclusions Results support the theoretical assumption of allostatic load mediating the effect of physical abuse during childhood on depression in adulthood. This predominantly holds for younger participants, while depression in older participants was independent of physical abuse and allostatic load. The effect of sexual abuse on depression, however, was not mediated by allostatic load. Identifying allostatic load biomarkers prospectively in the developmental course of depression is an important target for future research.

Maladaptive emotion regulation strategies, such as rumination and catastrophizing, are transdiagnostic risk factors for psychopathology. FK506-binding protein 51 (FKBP5) has been found to moderate the relationship between stressful life events and various psychiatric disorders. Given the cross-disorder moderation effect of FKBP5 at the diagnostic level, the aim of the current study was to examine whether the relationship between exposure to childhood trauma and transdiagnostic maladaptive emotion regulation processes would also be moderated by genetic FKBP5 variation in a community sample of adolescents. We hypothesized that adolescent carriers of the FKBP5 CATT haplotype composed of rs9296158, rs3800373, rs1360780, and rs9470080, that has been associated with increased risk for psychiatric disorders in adulthood, would also show higher levels of rumination and catastrophizing. Participants included 1345 genotyped adolescents (Mage=13.95, 64.2% female; 100% European Caucasians of Portuguese descent) who completed self-report measures on exposure to childhood trauma and emotion regulation strategies. Genotypes of rs9296158, rs3800373, rs1360780, and rs9470080 were used to estimate the CATT haplotype (carriers versus non-carriers). Consistent with our hypotheses and previous findings, adolescent CATT haplotype carriers with higher levels of childhood trauma endorsed higher levels of both rumination and catastrophizing compared to non-carriers. Given the association of these maladaptive emotion regulation processes and psychiatric disorders, the findings suggest possible psychological mechanisms why FKBP5 haplotype carriers exposed to childhood trauma are more vulnerable to developing a psychiatric disorder later in life.

Background Epigenetic modifications, in particular DNA methylation, play an important role in many biological processes in human health and disease. Understanding the cause of inter-individual differences in DNA methylation levels may help to identify novel molecular mechanisms contributing to a number of human diseases, including psychiatric diseases. Methods The aim of this study was to determine whether environmental risk factors for major depression (child abuse, socioeconomic status), genotype, or their interaction (GxE) best explain variablity in DNA methylation. We analyzed genome-wide DNA methylation (Illumina 450k arrays) from whole blood and genotype data of four independent cohorts (total N=1,.253). The cohorts consisted of adult individuals with diverse ethnic backgrounds, ages, and psychiatric disease status. Results We first identified the 15% most variably methylated (vm) CpGs in each cohort and observed that these vmCpGs had a higher correlation with brain methylation levels than expected by chance. Additionally, they were enriched in regulatory regions (including enhancer regions and specific, transcription factor binding sites). 40% (n=25.042) of the vmCpgGs overlapped between all 4 cohorts. We next analyzed, which factors explained most of the variance in methylation of these CpGs. While genotype alone explained most of the variance of about 20% of the vmCpGs, the majority of the vmCpGs were best explained by GxE (74%). E alone was almost never the model explaining most variance. We then investigated, how consistent the GxE effects on DNA methylation were across the 4 cohorts. We found that 30% of the vmCpGs were best explained by GxE in all four cohorts and 74% in at least three cohorts. The CpGs with GxE effects in all 4 cohorts also showed even stronger enrichment for enhancer regions than vmCpGs overall. Discussion Our study highlights the importance of considering both genetic and environmental data in interpreting epigenetic variation and suggests that integrating genotypes with epigenetic information could contribute to identifying functional genetic variants that moderate the impact of risk environments on the development of psychiatric disorders.