Identification of a schizophrenia-associated functional noncoding variant in NOS1AP

Area of Science:

• Neurogenetics
• Molecular Psychiatry

Background:

• Previous studies indicated a significant association between NOS1AP gene markers and schizophrenia in Canadian families.
• Elevated NOS1AP gene expression was observed in the dorsolateral prefrontal cortex of schizophrenia patients.

Purpose of the Study:

• To pinpoint specific risk alleles within the NOS1AP gene associated with schizophrenia.
• To investigate the functional mechanisms underlying the association between NOS1AP and schizophrenia.

Main Methods:

• Utilized posterior probability of linkage disequilibrium (PPLD) to evaluate 60 single nucleotide polymorphisms (SNPs) in NOS1AP within 24 Canadian families.
• Assessed regulatory function of identified SNPs using luciferase reporter assays in human neural cell lines (SK-N-MC and PFSK-1).
• Examined nuclear protein binding alterations in response to allelic variation via electrophoretic mobility shift assay.

Main Results:

• Three SNPs yielded PPLDs exceeding 40%, with rs12742393 showing significant allelic expression differences in both tested cell lines.
• Allelic variation at rs12742393 demonstrably altered nuclear protein binding affinity.
• The A allele of rs12742393 was linked to increased gene expression.

Conclusions:

• The A allele of rs12742393 is identified as a schizophrenia risk allele.
• This risk allele functions by enhancing transcription factor binding, leading to increased NOS1AP gene expression.
• Findings provide a molecular mechanism linking NOS1AP genetic variation to schizophrenia pathogenesis.