️ Episode 110: Whole-exome sequencing identifies new schizophrenia risk genes

In this episode of PaperCast Base by Base, we explore a landmark whole-exome sequencing study that expands our understanding of the rare genetic variants contributing to schizophrenia risk. By combining newly sequenced samples with large-scale published datasets, researchers provide the most comprehensive analysis to date of rare coding variants in this psychiatric disorder.

Study Highlights:
The study analyzed exome sequencing data from 4,650 new schizophrenia cases and 5,719 controls, which were combined with previously published datasets totaling nearly 29,000 cases, over 103,000 controls, and 3,444 proband-parent trios. Using meta-analysis, researchers identified exome-wide significant associations for two genes, STAG1 and ZNF136, strengthening prior evidence of their role in schizophrenia. Six additional genes reached statistical support at a false discovery rate below 5%, including SLC6A1 and KLC1, which were associated with damaging missense variants. The implicated genes overlap with those involved in neurodevelopmental and psychiatric disorders such as autism, developmental delay, and epilepsy. These findings highlight the convergence of rare coding variants with common variant signals and structural variation, particularly in pathways related to chromatin organization and neuronal signaling.

Conclusion:
This study advances the genetic landscape of schizophrenia by implicating new risk genes, underscoring the importance of rare coding variants and offering insights into disease mechanisms with potential relevance for future precision psychiatry.

Reference:
Chick, S. L., Holmans, P., Cameron, D., Grozeva, D., Sims, R., Williams, J., Bray, N. J., Owen, M. J., O’Donovan, M. C., Walters, J. T. R., & Rees, E. (2025). Whole-exome sequencing analysis identifies risk genes for schizophrenia. *Nature Communications, 16*, 7102. https://doi.org/10.1038/s41467-025-62429-y

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

Support:
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Keywords: schizophrenia, rare coding variants, whole-exome sequencing, STAG1, SLC6A1