Converging evidence implicates the abnormal microRNA system in schizophrenia.

Area of Science:

• Neurogenetics
• Molecular Biology
• Developmental Neuroscience

Background:

• Converging evidence suggests a link between schizophrenia (SZ) and impaired microRNA (miRNA) regulation during brain development.
• Previous research findings on this association have been inconsistent.

Purpose of the Study:

• To investigate the frequency of rare variants (RVs) in miRNA-related genes in SZ cases versus controls.
• To profile genome-wide miRNA expression in early-onset SZ (EOS) patients.
• To construct a miRNA-mRNA regulatory network in EOS.

Main Methods:

• Compared RVs in 59 miRNA-associated genes across GWAS data from 768 SZ cases/1348 controls and 1802 SZ cases/1447 controls.
• Performed genome-wide miRNA expression profiling in blood from 15 EOS cases and 15 controls.
• Constructed a miRNA-mRNA regulatory network using prior mRNA expression data from 18 EOS cases/12 controls.

Main Results:

• Found approximately 50% more RVs in miRNA-associated genes in SZ cases (P ≤ 2.62E-10).
• Observed significantly lower miRNA activity in EOS patients compared to controls, indicating downregulation.
• Identified a predicted regulatory network involving downregulated miRNAs and upregulated mRNAs.

Conclusions:

• Genetically based dysregulation of miRNA systems in SZ undermines miRNA inhibitory functions.
• This leads to abnormal upregulation of genome transcription during schizophrenia development.
• Findings support a significant role for miRNA system dysregulation in the pathogenesis of SZ.