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.

Figure 1

Comparison between people with schizophrenia and controls in peripheral blood cohort. (a) The relative expression levels of the seven-miRNA in the peripheral blood cohort of controls (Cn) (n=37, hollow circles) and people with schizophrenia (Sz) (n=48, solid circles) at acute state (T1), *P<0.05 and ***P<0.001. (b) The area under receiver operating characteristic curve (AUC) of the seven-miRNA signature in distinguishing the Sz and Cn.

Figure 2

The expression levels of the seven-miRNA in the peripheral blood cohort at acute (T1) and partial remission stage (T2) in people with schizophrenia (Sz, n=48). The seven miRNAs were not substantially altered between T1 and T2 of people with schizophrenia.

Figure 3

(a) Expression levels of hsa-miR-34a in BA46 and caudate of healthy control (Cn, n=27) and people with schizophrenia (Sz, n=25). (b) Expression levels of hsa-miR-34a in BA46 and caudate of non-psychiatric controls (Cn for short DOI, n=13; Cn for long DOI, n=14) and people with schizophrenia with short (Short Sz, n=13, solid square) or long duration of illness (Long Sz, n=12, solid triangle) *P < 0.05.

Figure 4

Scatter plot of age and hsa-miR-34a expression levels in BA46 (a) of people with schizophrenia (n=23) and (b) healthy controls (n=26) and in PBMCs of (c) people with schizophrenia (n=43) and (d) healthy controls (n=34). The correlation coefficient and its P-value were indicated by r and p, respectively.