GxTs in a dish suggest a treatment target that has already demonstrated efficacy in model systems and human populations. We're interested in pursuing this model more broadly to answer pharmacogenomics and gene x environment interactions. Thanks for reading!

Interesting because folate supplementation in mice rescues VPA induced teratogenicity and dietary folate supplementation in mothers taking antiepileptics, including VPA, is also associated with reduced autism diagnosis in the exposed children.

When performing TWAS using Edu Attainment GWAS (imperfect proxy for cognitive ability) on gene expression during VPA exposure, many significantly associated genes were identified, which were enriched in folate metabolism.

Many common genetic variants impacted chromatin accessibility or gene expression in this population (black circles are significant interaction molQTLs). Showing that inherent genetic variation does impact response to drugs.

VPA also strongly shuts down proliferation, measured through an EdU assay, consistent with prenatal VPA exposure leading to microcephaly.

Genes differentially expressed due to VPA replicated previous work and were enriched in genes associated with autism through whole exome sequencing, again suggesting convergence.

We found GWAS heritability for ASD and intelligence was strongly enriched within peaks differentially accessible due to VPA exposure, suggesting a convergence of genetic and environmental factors.

We added VPA, an anticonvulsant and mood stabilizer where prenatal exposure is associated with intellectual disability and autism, as well as Li, used for treatment of bipolar disorder, to a population of genotyped human neural progenitors.

Pharmacogenomic studies aim to identify which genetic variants predict response to clinically useful drugs. While these studies have had some success, they face inherent difficulties due to confounding and often find genetic variants influencing drug metabolism rather than brain cell response.

Excited to share our new preprint on molecular gene x treatment interactions led by Jordan Valone, Brandon Le, and @nanamatoba.bsky.social. www.medrxiv.org/content/10.1.... Here, we tried to further develop the "pharmacogenomics in a dish" approach for psychiatry.