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

Overview

1. Max Planck Institute of Psychiatry, Department Genes and Environment,Munich, Germany
2. International Max Planck Research School for Translational Psychiatry,Munich, Germany
3. Institute of Computational Biology, Helmholtz Zentrum München,Neuherberg, Germany
4. Charles Perkins Centre, The University of Sydney,Sydney, Australia
5. Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine,Atlanta, USA

Abstract

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. A major challenge lies in interpreting the function of non-coding variants, which comprise the majority of GWAS hits, making it difficult to determine their functional consequences, particularly in identifying the target genes and cell types involved. We investigated the disruption and enhancement of transcription factor (TF) binding motifs by schizophrenia-associated GWAS SNPs in 15 cortical cell types of the human brain. We integrated single-nucleus ATAC-seq and RNA-seq data from 71 donors (36 affected by schizophrenia) with GWAS summary statistics to identify TF motifs whose binding affinities are altered by schizophrenia-associated SNPs. We found that risk alleles of schizophrenia-associated SNPs disrupt and enhance TF binding. Furthermore, we demonstrated that disrupted TF motifs can lead to altered expression of target genes, including NAGA in excitatory neurons and SNX19 in protoplasmic astrocytes. 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. These findings may inform the development of novel therapeutic strategies targeting specific regulatory mechanisms.

Supplementary Information: The online version contains supplementary material available at 10.1007/s00018-026-06177-2.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

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Data availability

The computational code developed for this study has been made available on GitHub at https://github.molgen.mpg.de/mpip/TFbinding_CorticalCells, while the preprocessed and raw single-nuclei data is available at GEO (accession number RNA: GSE254569, accession number ATAC: GSE256207).

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 30 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 5 authors, 6 keywords, 11 MeSH terms, 1 funder, 49 references.

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This paper

Gerstner, N., Fröhlich, A. S., Matosin, N., Binder, E. B., & Knauer-Arloth, J. (2026). Schizophrenia risk variants modulate transcription factor binding and gene expression in cortical cell types. Cellular and molecular life sciences : CMLS, 83(1), 188. https://doi.org/10.1007/s00018-026-06177-2

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