Next steps for PTSD genomics: from loci to function

PROJECT SUMMARY/ABSTRACT Post-traumatic stress disorder (PTSD) is a severe mental disorder that develops in some victims of trauma but not all. Notably, the mechanisms underlying the development and pathophysiology of PTSD remain unknown, and reliable diagnostic biomarkers, as well as targeted therapeutic interventions, are still lacking. Our research team has employed genome-wide association studies (GWAS) to successfully identify PTSD risk loci as part of the Psychiatric Genomic Consortium for PTSD. We have also used and developed methods to link PTSD risk loci to molecular mechanisms for experimental follow-up. This proposal seeks to fine map the latest, robust PTSD risk loci by linking multi-omic and cell type- specific molecular mechanisms in the amygdala, hippocampus and prefrontal cortex, and specific PTSD-asso- ciated phenotypes. In Aim 1, we will identify causal variants and genes in the PTSD risk loci and conduct RNA expression, DNA methylation and protein expression analyses to identify region-specific and across-region gene networks associated with PTSD that involve causal variants and genes. In Aim 2, we will identify causal variants and genes in the PTSD risk loci at the brain cell type-specific level and gene molecular alterations across cell types associated with PTSD via single-nucleus (sn) RNA-seq- and Multiome-seq. We validate prioritized variants using in vitro with SNP-sepcific CRISPR-editing of induced pluripotent stem cells (iPSC) derived neural cultures exposed to glucocorticoids. In Aim 3, we will perform a phenomic characterization of the prioritized PTSD vari- ants, genes and networks resulting from Aims 1 and 2, explore PTSD subtypes based on implicated phenotypes, and evaluate associated polygenic risk scores to characterize the clinical significance of the fine-mapping ap- proaches. This study will greatly improve our understanding of the brain multi-omic and multi-cell type mechanisms, as well as phenomically characterize the causal risk variants, genes, and networks, and will point toward novel targets for intervention in PTSD.