Schizophrenia risk variants modulate transcription factor binding and gene expression in cortical cell types

Schizophrenia is a complex neuropsychiatric disorder with a strong genetic component. Genome-wide association studies (GWAS) have identified numerous risk variants, but their functional impact on gene regulation remains largely unknown. We investigate the disruption and enhancement of transcription factor (TF) binding motifs by schizophrenia-associated GWAS SNPs in 15 cortical cell types of the human brain. By integrating single-nucleus ATAC-seq and RNA-seq data from 71 donors (36 affected by schizophrenia) with GWAS summary statistics, we identify specific TF motifs whose binding affinities are altered by risk and protective SNPs. We find that risk SNPs predominantly disrupt TF binding, while protective SNPs show a more balanced effect. Furthermore, we demonstrate that disrupted TF motifs can lead to altered expression of target genes, including NAGA in excitatory neurons and HLA-B in oligodendrocyte precursor cells. These genes have been previously implicated in schizophrenia and our study provides a mechanism for their dysregulation through altered TF binding. Our findings highlight the importance of considering cell type-specific effects and provide a genome-wide map of TF motif disruptions in schizophrenia, offering insights into the regulatory mechanisms underlying disease risk.

This repository contains all scripts used for the analysis of TF binding disruption and enhancement through schizophrenia GWAS SNPs and the differential expression analysis of respective target genes between carriers and non-carriers of the respective alternative allele.