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Study Finds Role for MicroRNA in Schizophrenia Etiology

NEW YORK (GenomeWeb) – Researchers from the Schizophrenia Working Group of the Psychiatric Genomics Consortium have found that the microRNA miR-9-5p likely plays a part in schizophrenia etiology.

By drawing on data from a meta-analysis of more than 50 genome-wide association studies of schizophrenia, researchers led by Aarhus University's Manuel Mattheisen examined whether the hundred or so disease risk genes identified by the working group in 2014 are more likely to be regulated by miRNAs. As they reported today in JAMA Psychiatry, they further homed in on miR-9-5p, as it appears to regulate a number of schizophrenia risk genes, including FXR1, a homolog of the fragile X mental retardation 1 gene (FMR1).

"This study provides evidence for a role of miR-9-5p in the etiology of schizophrenia," the researchers wrote in their paper. "Its implication is of particular interest as the functions of this neurodevelopmental miRNA tie in with established disease biology."

Based on the summary statistics from the PGC2 GWAS meta-analysis, Mattheisen and his colleagues developed a linear model to test whether schizophrenia risk genes were more likely to be regulated by miRNAs.

They found that genes with more predicted miRNA targets did indeed have a stronger association with schizophrenia, on average. In particular, the 108 schizophrenia genes the consortium uncovered in 2014 had an average 21 percent excess of predicted miRNA-binding sites, as compared to protein coding genes in general.

Through gene set analyses, the researchers analyzed the targetomes of conserved miRNAs to find a number of schizophrenia-associated gene sets. The targetome of miR9-5p was particularly strongly associated with schizophrenia, Mattheisen and his colleagues reported.

Annotation of the miR9-5p gene set revealed that it is enriched for regulatory functions, brain development, and various transcription factors. The researchers further noted that expression of the gene set peaks across all brain regions at about the 16th week post-conception.

A cluster analysis using brain expression data from BrainSpan homed in on a set of 497 genes from within the miR9-5p gene set that were enriched for protein-protein interactions and schizophrenia risk genes as compared to randomly selected subsets of the miR9-5p gene set.

The targetomes of miR-485-5p and miR-137, which has previously been implicated in schizophrenia, were also strongly associated with the disorder, the researchers reported. They also noted that the targetomes of miR9-5p and miR-137 share a number of genes, though the overlap was not significant.

Previous studies had found that miR9-5p regulates neuronal differentiation and that it targets the dopamine D2 receptor, a common schizophrenia treatment target, the researchers noted. At the same time, it also targets FXR1, which has been shown to regulate miR9-5p levels and to play a key part of pre-miR9-5p processing. FMR1 itself, the researchers added, has been linked to schizophrenia in multiple studies.

The expression pattern for MIR9-2, one of the three genes that encode miR9-5p, in neuronal progenitor cells also underscores its neurodevelopmental role.

"[W]e identified a tripartite correlation between schizophrenia, miR-9-5p, and FMR1/FXR1 with the corollary that establishing the functional overlaps and differences between FMR1 and its homologues could potentially shed light on both the function of miR-9-5p and the etiology of schizophrenia," Mattheisen and his colleagues wrote.