Novel GxE effects and resilience: A case:control longitudinal study of psychosocial stress with war-affected youth.

Responses to early life adversity differ greatly across individuals. Elucidating which factors underlie this variation can help us better understand how to improve health trajectories. Here we used a case:control study of refugee and non-refugee youth, differentially exposed to war-related trauma, to investigate the effects of genetics and psychosocial environment on response to trauma. We investigated genetic variants in two genes (serotonin transporter, 5-HTT, and catechol-O-methyltransferase, COMT) that have been implicated in response to trauma. We collected buccal samples and survey data from 417 Syrian refugee and 306 Jordanian non-refugee youth who were enrolled in a randomized controlled trial to evaluate a mental health-focused intervention. Measures of lifetime trauma exposure, resilience, and six mental health and psychosocial stress outcomes were collected at three time points: baseline, ~13 weeks, and ~48 weeks. We used multilevel models to identify gene x environment (GxE) interactions and direct effects of the genetic variants in association with the six outcome measures over time. We did not identify any interactions with trauma exposure, but we did identify GxE interactions with both genes and resilience; 1) individuals with high expression (HE) variants of 5-HTTLPR and high levels of resilience had the lowest levels of perceived stress and 2) individuals homozygous for the Val variant of COMT with high levels of resilience showed stable levels of post-traumatic stress symptoms. We also identified a direct protective effect of 5-HTTLPR HE homozygotes on perceived insecurity. Our results point to novel interactions between the protective effects of genetic variants and resilience, lending support to ideas of differential susceptibility and altered stress reactivity in a cohort of war-affected adolescents.

Association of MAOA genetic variants and resilience with psychosocial stress: A longitudinal study of Syrian refugees.

Early childhood trauma can have profound and lifelong effects on adult mental health and psychosocial wellbeing. Nevertheless, responses to trauma are highly variable. Genetic variants may help explain variation in responses to trauma by identifying alleles that associate with changes in mental health measures. Protective factors, such as resilience, likely also play an important role in responses to trauma. The effects of genetic variants, in combination with protective factors, on psychosocial health are not well understood, particularly in non-Western contexts. In this study, we test the relative influence of genetic variants of monoamine oxidase A (MAOA, a gene proposed to influence the impact of childhood trauma on adult violence and antisocial behavior), levels of resilience, and exposure to traumatic events on psychosocial stress and mental health trajectories over time. We use data from a cohort of 12-18-year-old Syrian refugees who were forcibly displaced to neighboring Jordan (n = 399). DNA samples and survey data on trauma exposure, resilience (CYRM-12), and psychosocial stress were collected at three time points: baseline, ~13 weeks, and ~48 weeks. Using multilevel models, we identified an association of MAOA variant, in males only, with symptom scores of psychosocial stress on the Perceived Stress Scale (PSS) over time (p = 8.1 x 10-4). We also found that resilience is strongly associated with PSS (p = 7.9 x 10-9), underscoring the importance of protective factors in influencing levels of psychosocial stress. Furthermore, there was an additive effect wherein the sharpest reductions in perceived psychosocial stress are seen in low-activity MAOA males with low trauma exposure or high resilience levels. Our results highlight the value of studies that integrate genetic and psychosocial factors to better understand complex phenotypes, such as responses to trauma in contexts of high trauma exposure.

Associations between Maternal Psychosocial Stress, DNA Methylation, and Newborn Birth Weight Identified by Investigating Methylation at Individual, Regional, and Genome Levels.

Stress is known to affect health throughout life and into future generations, but the underlying molecular mechanisms are unknown. We tested the hypothesis that maternal psychosocial stress influences DNA methylation (DNAm), which in turn impacts newborn health outcomes. Specifically, we analyzed DNAm at individual, regional, and genome-wide levels to test for associations with maternal stress and newborn birth weight. Maternal venous blood and newborn cord blood (n = 24 and 22, respectively) were assayed for methylation at ∼450,000 CpG sites. Methylation was analyzed by examining CpG sites individually in an epigenome-wide association study (EWAS), as regional groups using variably methylated region (VMR) analysis in maternal blood only, and through the epigenome-wide measures using genome-wide mean methylation (GMM), Horvath's epigenetic clock, and mitotic age. These methylation measures were tested for association with three measures of maternal stress (maternal war trauma, chronic stress, and experience of sexual violence) and one health outcome (newborn birth weight). We observed that maternal experiences of war trauma, chronic stress, and sexual assault were each associated with decreased newborn birth weight (p < 1.95 × 10-7 in all cases). Testing individual CpG sites using EWAS, we observed no associations between DNAm and any measure of maternal stress or newborn birth weight in either maternal or cord blood, after Bonferroni multiple testing correction. However, the top-ranked CpG site in maternal blood that associated with maternal chronic stress and sexual violence before multiple testing correction is located near the SPON1 gene. Testing at a regional level, we found increased methylation of a VMR in maternal blood near SPON1 that was associated with chronic stress and sexual violence after Bonferroni multiple testing correction (p = 1.95 × 10-7 and 8.3 × 10-6, respectively). At the epigenomic level, cord blood GMM was associated with significantly higher levels of war trauma (p = 0.025) and was suggestively associated with sexual violence (p = 0.053). The other two epigenome-wide measures were not associated with maternal stress or newborn birth weight in either tissue type. Despite our small sample size, we identified associations even after conservative multiple testing correction. Specifically, we found associations between DNAm and the three measures of maternal stress across both tissues; specifically, a VMR in maternal blood and GMM in cord blood were both associated with different measures of maternal stress. The association of cord blood GMM, but not maternal blood GMM, with maternal stress may suggest different responses to stress in mother and newborn. It is noteworthy that we found associations only when CpG sites were analyzed in aggregate, either as VMRs or as a broad summary measure of GMM.

DNA methylation of methylation complex genes in relation to stress and genome-wide methylation in mother-newborn dyads.

OBJECTIVES: Early life stress is known to have enduring biological effects, particularly with respect to health. Epigenetic modifications, such as DNA methylation, are a possible mechanism to mediate the biological effect of stress. We previously found correlations between maternal stress, newborn birthweight, and genome-wide measures of DNA methylation. Here we investigate ten genes related to the methylation/demethylation complex in order to better understand the impact of stress on health. MATERIALS AND METHODS: DNA methylation and genetic variants at methylation/demethylation genes were assayed. Mean methylation measures were constructed for each gene and tested, in addition to genetic variants, for association with maternal stress measures based on interview and survey data (chronic stress and war trauma), maternal venous, and newborn cord genome-wide mean methylation (GMM), and birthweight. RESULTS: After cell type correction, we found multiple pairwise associations between war trauma, maternal GMM, maternal methylation at DNMT1, DNMT3A, TET3, and MBD2, and birthweight. CONCLUSIONS: The association of maternal GMM and maternal methylation at DNMT1, DNMT3A, TET3, and MBD2 is consistent with the role of these genes in establishing, maintaining and altering genome-wide methylation patterns, in some cases in response to stress. DNMT1 produces one of the primary enzymes that reproduces methylation patterns during DNA replication. DNMT3A and TET3 have been implicated in genome-wide hypomethylation in response to glucocorticoid hormones. Although we cannot determine the directionality of the genic and genome-wide changes in methylation, our results suggest that altered methylation of specific methylation genes may be part of the molecular mechanism underlying the human biological response to stress.

Genetic Loci and Novel Discrimination Measures Associated with Blood Pressure Variation in African Americans Living in Tallahassee.

Sequencing of the human genome and decades of genetic association and linkage studies have dramatically improved our understanding of the etiology of many diseases. However, the multiple causes of complex diseases are still not well understood, in part because genetic and sociocultural risk factors are not typically investigated concurrently. Hypertension is a leading risk factor for cardiovascular disease and afflicts more African Americans than any other racially defined group in the US. Few genetic loci for hypertension have been replicated across populations, which may reflect population-specific differences in genetic variants and/or inattention to relevant sociocultural factors. Discrimination is a salient sociocultural risk factor for poor health and has been associated with hypertension. Here we use a biocultural approach to study blood pressure (BP) variation in African Americans living in Tallahassee, Florida by genotyping over 30,000 single nucleotide polymorphisms (SNPs) and capturing experiences of discrimination using novel measures of unfair treatment of self and others (n = 157). We perform a joint admixture and genetic association analysis for BP that prioritizes regions of the genome with African ancestry. We only report significant SNPs that were confirmed through our simulation analyses, which were performed to determine the false positive rate. We identify eight significant SNPs in five genes that were previously associated with cardiovascular diseases. When we include measures of unfair treatment and test for interactions between SNPs and unfair treatment, we identify a new class of genes involved in multiple phenotypes including psychosocial distress and mood disorders. Our results suggest that inclusion of culturally relevant stress measures, like unfair treatment in African Americans, may reveal new genes and biological pathways relevant to the etiology of hypertension, and may also improve our understanding of the complexity of gene-environment interactions that underlie complex diseases.