Identification of Schizophrenia-Risk Regulatory Variant rs1399178 in the Non-coding Region With Its Impact on NRF1 Binding

Abstract

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.