Article Impact Level: HIGH Data Quality: STRONG Summary of Cell, S0092867424014351. https://doi.org/10.1016/j.cell.2024.12.022 Dr. Sool Lee et al.
Points
- A GWAS identified 136 genetic “hot spots” linked to eight psychiatric disorders, with 109 shared across multiple conditions, indicating a common genetic foundation.
- Researchers tested 17,841 variants from these hot spots, finding 683 that influenced gene regulation in neural cells, including pleiotropic variants shared across disorders and disorder-specific variants.
- Pleiotropic variants were highly active and influenced genes involved in critical processes like protein production, synapse formation, and neuronal development, affecting multiple psychiatric disorders.
- Genes associated with pleiotropic variants were highly interconnected in protein-protein interaction networks, suggesting widespread effects on brain function when disrupted.
- The findings highlight pleiotropic variants as promising therapeutic targets for multiple psychiatric disorders, paving the way for treatments addressing shared genetic pathways.
Summary
In a study published in Cell, researchers investigated the genetic basis of pleiotropy in psychiatric disorders, focusing on variants that affect multiple conditions. A previous genome-wide association study (GWAS) identified 136 genetic “hot spots” linked to eight psychiatric disorders, including autism spectrum disorder, schizophrenia, and bipolar disorder. Notably, 109 hot spots were shared across multiple disorders, suggesting a shared genetic foundation. Using a massively parallel reporter assay, researchers tested 17,841 variants from these hot spots in human neural cells, identifying 683 variants that influenced gene regulation. These variants were classified into pleiotropic variants (shared across multiple disorders) and disorder-specific variants. The study found that pleiotropic variants were more active and sensitive to change, influencing gene expression during multiple stages of neurodevelopment.
The study further explored the functional consequences of pleiotropic variants, highlighting their extended roles in neuronal development. Pleiotropic variants were shown to affect genes involved in protein production and synapse formation, critical for brain development and function. These variants also impacted protein-protein interaction networks, amplifying their potential to influence multiple psychiatric disorders. The researchers found that the genes associated with pleiotropic variants were more interconnected in protein networks, suggesting that disruptions to these genes could lead to widespread effects on brain function.
Overall, the findings underscore the potential of pleiotropic variants as therapeutic targets for multiple psychiatric disorders. The study’s approach suggests that understanding the genetic basis of pleiotropy could lead to treatments that address several conditions simultaneously. This research paves the way for more precise interventions in psychiatric care, focusing on shared genetic factors that contribute to a range of disorders. These insights could significantly improve treatment strategies and patient outcomes by targeting common genetic pathways.
Link to the article: https://www.cell.com/cell/fulltext/S0092-8674(24)01435-1
References Lee, S., McAfee, J. C., Lee, J., Gomez, A., Ledford, A. T., Clarke, D., Min, H., Gerstein, M. B., Boyle, A. P., Sullivan, P. F., Beltran, A. S., & Won, H. (2025). Massively parallel reporter assay investigates shared genetic variants of eight psychiatric disorders. Cell, S0092867424014351. https://doi.org/10.1016/j.cell.2024.12.022
