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

Area of Science:

• Neurogenetics
• Molecular Psychiatry
• Genomic Regulation

Background:

• Schizophrenia has a significant genetic basis, identified through Genome-Wide Association Studies (GWAS).
• Interpreting the functional role of non-coding genetic variants, common in GWAS, is challenging.
• Understanding how these variants affect gene regulation in specific brain cell types is crucial.

Purpose of the Study:

• To investigate how schizophrenia-associated single nucleotide polymorphisms (SNPs) disrupt or enhance transcription factor (TF) binding motifs.
• To identify cell type-specific regulatory mechanisms affected by these genetic variants in the human brain cortex.
• To link altered TF binding to the dysregulation of target genes implicated in schizophrenia.

Main Methods:

• Integrated single-nucleus ATAC-seq and RNA-seq data from 71 human brain donors (36 with schizophrenia).
• Analyzed GWAS summary statistics to identify TF motifs affected by schizophrenia-associated SNPs.
• Mapped TF motif disruptions across 15 distinct cortical cell types.

Main Results:

• Schizophrenia-associated SNPs were found to both disrupt and enhance TF binding affinities.
• Altered TF binding led to changes in the expression of target genes, such as NAGA in excitatory neurons and SNX19 in protoplasmic astrocytes.
• Identified specific genes and cell types where TF binding alterations contribute to schizophrenia risk.

Conclusions:

• Genetic variants associated with schizophrenia can alter TF binding, leading to gene expression changes in a cell type-specific manner.
• This provides a mechanistic link between genetic risk factors and gene dysregulation in schizophrenia.
• The findings offer a genome-wide map of TF motif disruptions and inform potential therapeutic targets.