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Gerstner, N. ; Fröhlich, A.S.* ; Matosin, N.* ; Binder, E.B.* ; Knauer-Arloth, J.

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

Cell. Mol. Life Sci. 83:188 (2026)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Cell Type ; Genetic Variants ; Motif Alterations ; Orbitofrontal Cortex ; Schizophrenia ; Transcription Factor Binding
ISSN (print) / ISBN 1420-682X
e-ISSN 1420-9071
Zeitschrift Cellular and Molecular Life Sciences - CMLS
Quellenangaben Band: 83, Heft: 1, Seiten: , Artikelnummer: 188 Supplement: ,
Verlag Springer
Verlagsort Picassoplatz 4, Basel, 4052, Switzerland
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)
Förderungen Max Planck Institute of Psychiatry (2)