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Updated: Apr 6, 2026
Chemogenetic Regulation in Reprogrammed Stem Cell-derived Precursor Cells in Treating Neurodegenerative Diseases
Published on: May 2, 2025
Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid
Jordan M Valone1,2, Brandon D Le1,2, Nana Matoba1,2
1Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Abstract:
Gene by treatment (GxT) interactions likely contribute to variability in clinical response, but are difficult to identify in population studies. Here, we applied psychiatric and neurological disorder treatments to a genotyped population of human neural progenitors (n = 83 donors) and measured molecular responses on chromatin accessibility and gene expression. Gene regulatory responses to valproic acid (VPA), which is also a prenatal risk factor for autism, and lithium were highly enriched in genetic risk for psychiatric disorders, demonstrating the convergence of environmental and genetic factors. Genetic variation impacted molecular response to these drugs at over 1000 loci, a subset of which modulated the impacts of psychiatric risk variants. Finally, transcriptome-wide association conducted in the context of VPA revealed genes involved with folate metabolism associated with cognitive ability. As previous work has shown that folate supplementation can alleviate VPA-induced teratogenic effects, this approach identified a validated treatment pathway supporting its broad utility.
Insights
Investigating gene by treatment interactions in neural progenitors revealed how genetic variations impact drug responses. This study identified a folate metabolism pathway linked to cognitive ability, offering a potential therapeutic target for valproic acid effects.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Gene by treatment (GxT) interactions are crucial for understanding individual responses to psychiatric and neurological treatments.
- Identifying GxT interactions in population studies is challenging due to complex molecular responses.
Purpose of the Study:
- To investigate GxT interactions in human neural progenitors using psychiatric and neurological treatments.
- To identify genetic factors influencing molecular responses to drugs like valproic acid (VPA) and lithium.
- To explore the link between genetic variation, drug response, and psychiatric risk.
Main Methods:
- Applied psychiatric and neurological disorder treatments to a genotyped population of 83 human neural progenitor cell donors.
- Measured molecular responses including chromatin accessibility and gene expression.
- Utilized transcriptome-wide association studies (TWAS) in the context of VPA treatment.
Main Results:
- Gene regulatory responses to VPA and lithium were enriched in genetic risk for psychiatric disorders.
- Genetic variation impacted molecular responses at over 1000 loci, with some variants modulating psychiatric risk.
- TWAS identified genes in folate metabolism associated with cognitive ability under VPA exposure.
Conclusions:
- Demonstrated the convergence of environmental and genetic factors in psychiatric disorders.
- Identified a validated treatment pathway involving folate metabolism for VPA-induced effects.
- Highlighted the utility of studying GxT interactions in neural progenitors for drug discovery and personalized medicine.
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