AIMS: The challenges in identifying functional variants from genome-wide association studies (GWAS) and unraveling regulatory mechanisms in schizophrenia research persist, particularly in intronic regions. A non-coding regulatory variant, rs1399178, associated with schizophrenia risk, is identified and its impact on NRF1 binding is investigated. METHODS: This study focuses on schizophrenia GWAS risk loci, using functional genomics, expression analyses and structural analysis to identify 736 schizophrenia risk single-nucleotide polymorphisms (SNPs) that disrupt transcription factor (TF) binding. RESULTS: Among these SNPs, rs1399178 stands out as a bifunctional intergenic SNP that can switch between acting as a promoter and an enhancer, potentially influencing MLH1 and LRRFIP2 expression via expression quantitative trait loci analysis. Importantly, mutation of the G allele of rs1399178 to A significantly diminishes its binding affinity to nuclear respiratory factor 1 (NRF1). Structural analysis provides further insight into this alteration in the protein-nucleic acid complex formation. CONCLUSION: Based on our data, a model is proposed in which rs1399178 confers schizophrenia risk by modifying NRF1 binding profiles, thereby regulating the abundance of target genes through promoter-enhancer switching. This study provides novel insights into the regulatory mechanisms of schizophrenia risk variants, highlighting the intricate nature of genetic interactions and potential therapeutic targets.