Aberrant expression of microRNAs as biomarker for schizophrenia: from acute state to partial remission, and from peripheral blood to cortical tissue

Abstract

Based on our previous finding of a seven-miRNA (hsa-miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572 and miR-652) signature as a potential biomarker for schizophrenia, this study aimed to examine if hospitalization could affect expressions of these miRNAs. We compared their expression levels between acute state and partial remission state in people with schizophrenia (n=48) using quantitative PCR method. Further, to examine whether the blood and brain show similar expression patterns, the expressions of two miRNAs (hsa-miR-34a and hsa-miR-548d) were examined in the postmortem brain tissue of people with schizophrenia (n=25) and controls (n=27). The expression level of the seven miRNAs did not alter after ~2 months of hospitalization with significant improvement in clinical symptoms, suggesting the miRNAs could be traits rather than state-dependent markers. The aberrant expression seen in the blood of hsa-miR-34a and hsa-miR-548d were not present in the brain samples, but this does not discount the possibility that the peripheral miRNAs could be clinically useful biomarkers for schizophrenia. Unexpectedly, we found an age-dependent increase in hsa-miR-34a expressions in human cortical (Brodmann area 46 (BA46)) but not subcortical region (caudate putamen). The correlation between hsa-miR-34a expression level in BA46 and age was much stronger in the controls than in the cases, and the corresponding correlation in the blood was only seen in the cases. The association between the miRNA dysregulations, the disease predisposition and aging warrants further investigation. Taken together, this study provides further insight on the candidate peripheral miRNAs as stable biomarkers for the diagnostics of schizophrenia.

Systemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions

“…60 Additionally, 29%-34% of the genes that were correlated with age in healthy subjects were dysregulated in subjects with early-stage schizophrenia. On the other hand, neither hsa-miR-34a expression 22 nor histone acetylation levels 61 were associated with age in schizophrenia. Association With Other Factors Levels of hsa-miR-34a were higher in patients with longer than shorter duration of illness with large effect sizes, suggesting that this microRNA may increase with disease severity.…”

“…In the clinical sample cohort, hsa-miR34a significantly interacted with age such that expression seemed to increase among patients with schizophrenia compared to an apparent age-related decline in HCs. 22 Additionally, in genome-wide expression profiles from the human frontal cortex, the relative expression levels of genes most significantly correlated with age were different between younger and older HCs but not in schizophrenia patients, suggesting that patients express a higher level of age-related genes throughout their lifespan. 60 Additionally, 29%-34% of the genes that were correlated with age in healthy subjects were dysregulated in subjects with early-stage schizophrenia.…”

“…Levels of hsa-miR-34a and hsamiR449a microRNAs, previously identified to be potential biomarkers for schizophrenia, were higher in patients with schizophrenia compared to HCs in a human sample, with medium to large effect sizes; however, in a post-mortem sample, no differences were observed between the groups. 22 Additionally, individuals with schizophrenia exhibited decreased expression of 5 neuronally expressed genes, HTR2C (serotonin 5-hydroxytryptamine receptor 2C), TOMM70A (mitochondrial function/import), RGS4 (regulator of G protein signaling 4), PPM1E (protein phosphatase, Mg2+/Mn2+ dependent, 1E), and GAD1 (GABAergic neurotransmission), compared to HCs; no difference in histone acetylation (Ac-H3K9K14) levels in these gene promoter regions was detected. 61 Age Relationships Fifty percent of gene expression and regulation studies found steeper age relationships in schizophrenia.…”

“…In total, 82 full-text articles were assessed for eligibility, and 41 met the above-mentioned criteria for review. One article 22 reported on 2 experiments with different sample cohorts and biomarker samples, so this publication was counted twice as separate studies to make a total of 42 included studies. The PRISMA flow chart depicting information through different stages of the systematic review is shown in figure 1.…”

“…whereas 29% examined systemic markers in postmortem brain tissue. 22,[53][54][55][56][57][58][59][60][61][62][63] Most studies investigated a mixed-age sample of adults, 2 included only older participants. 55,58 All reviewed studies had at least one comparison group: 34 compared schizophrenia patients to a nonpsychiatric HC group; 4 involved at least one psychiatric comparison group in addition to an HC group; 32,53,61,63 one included only psychiatric comparison groups 40 ; one compared subtypes of patients with schizophrenia.…”