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

## TL;DR

This study identifies a non-coding genetic variant linked to schizophrenia that affects a protein's binding, potentially influencing gene regulation and disease risk.

## Contribution

The paper introduces rs1399178 as a bifunctional regulatory variant impacting NRF1 binding and gene expression in schizophrenia.

## Key findings

- rs1399178 is a schizophrenia risk SNP that disrupts transcription factor binding and can act as both promoter and enhancer.
- Mutation of rs1399178 reduces its binding affinity to NRF1, altering gene regulation.
- The variant influences MLH1 and LRRFIP2 expression through promoter-enhancer switching.

## Abstract

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.

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.

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.

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.

The identification of rs1399178 as a bifunctional regulatory element, mediating promoter‐enhancer switch and interacting with NRF1, sheds light on the complex regulatory networks involved in schizophrenia pathogenesis.