Abstract
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 genes MED1, HSPA1L, GTF2A1 and TAF15, 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.
Highlights
Bipolar disorder (BD) is a devastating mental disorder with a prevalence of 1–2% and increased rates of several chronic comorbid medical conditions.[1]
While groups did not differ for age, gender, ethnicity, race, years of education or pubertal development (P40.05 for all comparisons), patients with pediatric BD presented significantly higher scores for Identification of risk genes and pathway analysis ‘Risk genes’ were identified as those genes that were concordant in the lists of differentially expressed genes or differentially methylated probes (DMPs) between controls versus high-risk offspring and controls versus BD patients
Uploaded into Ingenuity Pathway Analysis (IPA, Qiagen) for the assessment of enrichments in canonical pathways and networks. This was followed by literature and database mining to check for evidence of associations between the risk genes identified in our analysis and previous studies in BD patients
Summary
Bipolar disorder (BD) is a devastating mental disorder with a prevalence of 1–2% and increased rates of several chronic comorbid medical conditions.[1]. DNA methylation, being modulated by both genetic background[5] and environmental exposure,[6] may be a marker of risk/resilience and a trigger for the development of BD.[7] Further, DNA methylation can change the expression of the key genes, potentially contributing to disease susceptibility. Previous studies have suggested that the combined assessment of gene expression and methylation data outperforms either data modality in identifying disease susceptibility loci, even in relatively small sample sizes.[8] Of note, the study of such markers in peripheral blood cells is warranted, given the easy access to tissue allowing for longitudinal comparisons in high-risk subjects. Peripheral pathways, such as inflammatory and metabolic processes, have been consistently associated with BD and its risk,[9] and blood DNA methylation has been shown to correlate with brain volume[10] and symptoms of major psychiatric disorders, including depression[11] and BD.[12]
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