microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder

Abstract

Background: microRNAs (miRNAs) are small, noncoding RNA molecules that are now thought to regulate the expression of many mRNAs. They have been implicated in the etiology of a variety of complex diseases, including Tourette's syndrome, Fragile x syndrome, and several types of cancer.

Results: We hypothesized that schizophrenia might be associated with altered miRNA profiles. To investigate this possibility we compared the expression of 264 human miRNAs from postmortem prefrontal cortex tissue of individuals with schizophrenia (n = 13) or schizoaffective disorder (n = 2) to tissue of 21 psychiatrically unaffected individuals using a custom miRNA microarray. Allowing a 5% false discovery rate, we found that 16 miRNAs were differentially expressed in prefrontal cortex of patient subjects, with 15 expressed at lower levels (fold change 0.63 to 0.89) and 1 at a higher level (fold change 1.77) than in the psychiatrically unaffected comparison subjects. The expression levels of 12 selected miRNAs were also determined by quantitative RT-PCR in our lab. For the eight miRNAs distinguished by being expressed at lower microarray levels in schizophrenia samples versus comparison samples, seven were also expressed at lower levels with quantitative RT-PCR.

Conclusion: This study is the first to find altered miRNA profiles in postmortem prefrontal cortex from schizophrenia patients.

Figure 1

An miRNA expression map shows differentiated genes as determined by SAM analysis. Yellow indicates low expression and blue indicates high expression, relative to the median.

Figure 2

miRNA microarray fold changes can be compared with delta-delta C(t) functions of qRT-PCR data (see Materials and methods). The comparisons are over four samples from schizophrenia patients and four samples from psychiatrically unaffected comparison subjects. Seven of the eight comparisons are consistent.

Figure 3

Regarding the 11 isolated miRNAs distinguished in schizophrenia, this figure shows the distances (numbers of bases) from shared 5' motifs we discovered (two 8 nt and two 12 nt motif sequences in the pri-miRNA) to the ssRNA-dsRNA junctions at starts of pre-miRNAs. Pre-miR-30a and -9-1 have double motif instances; second instances are in the rectangle. Ignoring the second instances as redundant leaves some motif distances in sharp clusters.

Figure 4

Transcription yields a continuous supply of some types of pri-miRNA transcripts, capped and polyadenylated. hnRNPs are hypothesized to shape the pri-miRNA into linear and hairpin sections. A signaling system somehow recruits and activates unknown factors that select particular pre-miRNA hairpins on a particular pri-miRNA for excision and processing in the miRNA pathway. We hypothesize that this system might include a binding motif. RNASEN and DGCR8 are products of genes 29102 and 54487.