A VNTR Regulates miR-137 Expression Through Novel Alternative Splicing and Contributes to Risk for Schizophrenia

Area of Science:

• Neurogenetics
• Molecular Psychiatry
• Genomics

Background:

• The MIR137HG gene, encoding microRNA-137 (miR-137), is linked to schizophrenia (SZ) risk, but the mechanisms are unclear.
• Novel splice variants of pri-miR-137, termed 'del-miR-137', lack mature miR-137 and may down-regulate its expression.

Purpose of the Study:

• To investigate novel MIR137HG splice variants and their association with schizophrenia risk.
• To explore the role of variable number tandem repeat (VNTR) elements in SZ susceptibility.

Main Methods:

• Cloning and sequencing of MIR137HG transcripts from human brain tissues.
• In-silico prediction of del-miR-137 function.
• Case-control haplotype analysis in a schizophrenia cohort (n=998).

Main Results:

• Novel del-miR-137 splice variants were identified, associated with VNTR length.
• Higher del-miR-137 proportion in fetal brain suggests neurodevelopmental regulation.
• Short VNTR length and specific recombination events were linked to increased SZ risk, while longer lengths showed a protective effect.

Conclusions:

• VNTR length and alternative MIR137HG transcripts represent a novel regulatory mechanism influencing SZ risk.
• These findings elucidate the complex genetic architecture of the miR-137 region in schizophrenia.