A miR-137-Related Biological Pathway of Risk for Schizophrenia Is Associated With Human Brain Emotion Processing

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• MicroRNA-137 (miR-137) is crucial for brain development, neurogenesis, and neuronal maturation.
• Genome-wide association studies link miR-137 to schizophrenia risk, but its precise role in brain function remains unclear.
• Previous research suggests miR-137 targets are associated with working memory and emotion processing in schizophrenia.

Purpose of the Study:

• To investigate the functional brain correlates of miR-137 target genes associated with schizophrenia.
• To differentiate the roles of miR-137 targets in working memory versus emotion processing.
• To explore the relationship between miR-137 expression, gene coexpression networks, and schizophrenia.

Main Methods:

• RNA sequencing analyzed postmortem prefrontal cortex samples (N=522) to identify a coexpression gene set enriched for miR-137 targets and schizophrenia risk genes.
• In vitro experiments manipulated miR-137 expression in neuroblastoma cells to validate gene set relationships.
• Polygenic scores derived from the gene set were associated with functional magnetic resonance imaging (fMRI) data in healthy volunteers and treatment response in schizophrenia patients.

Main Results:

• Schizophrenia risk genes were found to be coexpressed in a biologically validated set enriched for miR-137 targets across 4652 participants.
• Low prefrontal miR-137 expression mediated increased expression of miR-137 target risk genes.
• Alleles predicting greater gene set coexpression correlated with increased prefrontal activation during emotion processing in healthy individuals and predicted poorer treatment response in schizophrenia patients.

Conclusions:

• The study demonstrates that miR-137 target gene expression, implicated in schizophrenia, functionally involves the neural substrates of emotion processing.
• Findings highlight the role of miR-137 in modulating brain activity related to emotion processing and its impact on schizophrenia pathophysiology and treatment.