MicroRNA Correlates of Childhood Maltreatment and Suicidality

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The purpose of this project is to determine if the relationship between a history of childhood maltreatment (CM) and suicide risk is associated with alterations in the expression and epigenetic modification of specific microRNAs (miRNAs), thereby providing a molecular signature of suicide risk in people with a history of CM. We propose that whereas both major depressive disorder (MDD) and suicidality are complex phenotypes, CM alters the risk threshold for both. Epigenetic changes caused by early stressful events can induce long-term alterations affecting networks of genes. miRNA expression represents one of the central mechanisms for environmental regulation of gene expression. miRNA sequences themselves are epigenetically modified. The sum of these effects may explain long-term cellular (mal)adaptations which may lead to suicide vulnerability in the CM population. Using a specific cell surface marker, we isolated neural-derived exosomes from blood plasma and found that these exosomes were not only enriched with brain expressed miRNAs, but also showed a unique set of miRNAs that were associated with CM and suicidality. Changes in the same set of miRNAs were also noted in the brain of suicide subjects with a history of CM. In addition, suicidal subjects with and without CM showed differential regulation of miRNAs in response to acute stress, a short-term risk for suicidal behavior, particulay in the context of CM. Moreover, miRNA expression changes were highly correlated with exosomal miRNA promoter methylation. Based on our preliminary data, we propose an overarching hypothesis that there are multiple paths to suicidal behavior, and CM represents a unique path that is associated with altered expression and epigenetic modification of a specific set of miRNAs and concomitant downstream specific target genes and network(s). To test this, we will: 1) identify a set of neural-derived exosomal miRNAs that are associated with the interaction of suicidality and CM severity while controlling for the independent effects of suicidality, CM, and MDD; 2) examine whether an acute experimental stressor differentially impacts the expression of neural-derived exosomal miRNAs in suicidal patients with and without CM; 3) use bioinformatic tools to examine potential mechanisms by which altered neural-derived exosomal miRNAs may contribute to CM-associated suicidal behavior; and 4) examine if changes in CM-associated miRNAs are explained by modifications in their DNA methylation. In participants (n=450; replicated in a cohort of 350 subjects) across the spectrum of MDD, suicide, and CM severity, we will test for the main effects of each, and identify a subset of miRNAs that are associated with suicidality and CM severity. We will also test for the independent main effects of CM or suicidality on miRNAs and the interactions among those factors. Altogether, using a distinct study population, unique neural-derived plasma exosomes, and innovative molecular, biostatistical, and bioinformatic tools, our study will identify: 1) neural-derived plasma exosomal miRNAs as a novel biosignature of suicide risk in the context of CM that can be tested in longitudinal studies, and 2) potential mechanisms by which CM can act as a risk factor for suicidality.