Assessing molecular gene by treatment interactions using a population of neural progenitors exposed to valproic acid and lithium

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 1,000 loci, a subset of which modulated the impacts of psychiatric disorder risk variants. Finally, transcriptome-wide association revealed enzymes involved with folate metabolism during VPA exposure impact cognitive ability, a pathway previously shown to alleviate the negative impacts of this exposure. The “GxT in a dish” approach identified a validated treatment pathway, supporting its broad utility. Competing Interest Statement The authors have declared no competing interest. Funding Statement This study was supported by grants from the National Institute of Mental Health (NIMH) (R01MH118349, R01MH120125 and R01MH121433). J.M.V. and B.D.L. were supported, in part, by National Institutes of Health (NIH) T32 training grants (T32GM135123 and T32GM067553, respectively). Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UNC IRB determined that this study was IRB exempt (IRB number: 16-0054), due to the use of post-mortem tissue. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data and metadata generated for this study will be available via dbGaP; acccession number TBD. All code used in analyses and data including full summary statistics except that which is provided in supplementary tables will be available on bitbucket.