Background: Opioid use disorder (OUD) affects millions of people, causing nearly 50 000 deaths annually in the United States. While opioid exposure and OUD are known to cause widespread transcriptomic and epigenetic changes, few studies in human samples have been conducted. Understanding how OUD affects the brain at the molecular level could help decipher disease pathogenesis and shed light on OUD treatment.Methods: We generated genome-wide transcriptomic and DNA methylation profiles of 22 OUD subjects and 19 non-psychiatric controls. We applied weighted gene co-expression network analysis to identify genetic markers consistently associated with OUD at both transcriptomic and methylomic levels. We then performed functional enrichment for biological interpretation. We employed cross-omics analysis to uncover OUD-specific regulatory networks.Results: We found 6 OUD-associated co-expression gene modules and 6 co-methylation modules (false discovery rate <0.1). Genes in these modules are involved in astrocyte and glial cell differentiation, gliogenesis, response to organic substance, and response to cytokine (false discovery rate <0.05). Cross-omics analysis revealed immune-related transcription regulators, suggesting the role of transcription factor-targeted regulatory networks in OUD pathogenesis.Conclusions: Our integrative analysis of multi-omics data in OUD postmortem brain samples suggested complex gene regulatory mechanisms involved in OUD-associated expression patterns. Candidate genes and their upstream regulators revealed in astrocyte, and glial cells could provide new insights into OUD treatment development.

Human-induced pluripotent stem cells (hiPSCs) allow for the establishment of brain cellular models of psychiatric disorders that account for a patient’s genetic background. Here, we conducted an RNA-sequencing profiling study of hiPSC-derived cell lines from schizophrenia (SCZ) subjects, most of which are from a multiplex family, from the population isolate of the Central Valley of Costa Rica. hiPSCs, neural precursor cells, and cortical neurons derived from six healthy controls and seven SCZ subjects were generated using standard methodology. Transcriptome from these cells was obtained using Illumina HiSeq 2500, and differential expression analyses were performed using DESeq2 (|fold change|>1.5 and false discovery rate < 0.3), in patients compared to controls. We identified 454 differentially expressed genes in hiPSC-derived neurons, enriched in pathways including phosphoinositide 3-kinase/glycogen synthase kinase 3 (PI3K/GSK3) signaling, with serum-glucocorticoid kinase 1 (SGK1), an inhibitor of glycogen synthase kinase 3β, as part of this pathway. We further found that pharmacological inhibition of downstream effectors of the PI3K/GSK3 pathway, SGK1 and GSK3, induced alterations in levels of neurite markers βIII tubulin and fibroblast growth factor 12, with differential effects in patients compared to controls. While demonstrating the utility of hiPSCs derived from multiplex families to identify significant cell-specific gene network alterations in SCZ, these studies support a role for disruption of PI3K/GSK3 signaling as a risk factor for SCZ.

Objectives: Psychiatric and substance-use disorders have been associated with premature biological ageing. Telomere length (TL), considered an ageing marker, has been analysed in psychiatric disorders, and to a lesser extent in substance-use disorders, with recent findings suggesting TL may be related to disease pathology. Methods: We conducted a critical and non-systematic literature search of TL studies published up to June 2016 in psychiatric and substance-use disorders, focussing on studies describing mechanisms, including studies linking telomere biology with genetic factors, stress and mitochondrial alterations (104 studies selected). Results: Patients with major depressive disorder and anxiety appear to have shorter leukocyte telomeres compared to controls. Inconclusive results are found for other psychiatric disorders and for substance-use disorders. This may be due in part to differences in medication treatment and response, as studies suggest that some psychotropic medications may modulate TL. Importantly, some studies establish a relationship between telomere machinery, stress and mitochondria function in psychiatric and substance-use disorders. Conclusions: While further longitudinal studies considering telomere genetics are needed to clarify the cause–effect link between telomeres and mitochondria function in psychiatric and substance-use disorders, the recent findings linking these biological processes suggest that telomeres may be more than ageing markers.

First-degree relatives of patients with bipolar disorder (BD), particularly their offspring, have a higher risk of developing BD and other mental illnesses than the general population. However, the biological mechanisms underlying this increased risk are still unknown, particularly because most of the studies so far have been conducted in chronically ill adults and not in unaffected youth at high risk. In this preliminary study we analyzed genome-wide expression and methylation levels in peripheral blood mononuclear cells from children and adolescents from three matched groups: BD patients, unaffected offspring of bipolar parents (high risk) and controls (low risk). By integrating gene expression and DNA methylation and comparing the lists of differentially expressed genes and differentially methylated probes between groups, we were able to identify 43 risk genes that discriminate patients and high-risk youth from controls. Pathway analysis showed an enrichment of the glucocorticoid receptor (GR) pathway with the genesMED1,HSPA1L,GTF2A1andTAF15, which might underlie the previously reported role of stress response in the risk for BD in vulnerable populations. Cell-based assays indicate a GR hyporesponsiveness in cells from adult BD patients compared to controls and suggest that these GR-related genes can be modulated by DNA methylation, which poses the theoretical possibility of manipulating their expression as a means to counteract the familial risk presented by those subjects. Although preliminary, our results suggest the utility of peripheral measures in the identification of biomarkers of risk in high-risk populations and further emphasize the potential role of stress and DNA methylation in the risk for BD in youth.