Identification of Schizophrenia-Risk Regulatory Variant rs1399178 in the Non-coding Region With Its Impact on NRF1
Lei Ji1,2,3, Bojian Huang1,2,3, Decheng Ren1,2,3
1Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China.
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.
More Related Videos
09:34Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
09:52Generation of High Quality Chromatin Immunoprecipitation DNA Template for High-throughput Sequencing ChIP-seq
Published on: April 19, 2013
Related Concept Videos
Human Genetics
The complex relationship between genetics and psychology is observable through common biological components such...
Comparing Copy Number Variations and SNPs
Copy number variations or CNVs are the structural variations that cover more than 1kb of DNA sequence. The single nucleotide polymorphism (SNP), on the other hand, is a single nucleotide change or a point mutation that is found in more than 1%...
RNA Stability
Cis-regulatory Sequences
Single Nucleotide Polymorphisms-SNPs
Genome-wide Association Studies-GWAS
GWAS does not require the identification of the target gene involved in...
