Modeling gene x environment interactions in post-traumatic stress disorder.

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PROJECT SUMMARY Posttraumatic stress disorder (PTSD) is a common, debilitating disorder, triggered by exposure to a traumatic event. PTSD is often under-diagnosed and undertreated, despite early detection and treatment governing favorable outcomes. Better identification of elements of disorder susceptibility or resilience is important for prompt delivery of care to mitigate disorder burden. As PTSD has shown to be heritable, a prevailing theory of disorder susceptibility is genetic. Large-scale genome wide association studies (GWAS) have revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of 5-20%. Yet, environmental factors, such as childhood trauma, have also shown to independently predict PTSD development. Genome-wide integration of PTSD-associated genetic loci with stressful exposures may elucidate gene by environment interactions that influence disorder susceptibility. In this proposal, I will investigate loci with joint genetic and environmental contributions to PTSD risk, employing an integrative multi-level approach to examine and validate brain region and cell type-specific regulation. One major issue integrating GWAS findings with environmental exposures is the largely non-coding nature of GWAS-identified loci, obscuring clear functional ramifications. To overcome this, I will associate identified variants with nearby expression changes to uncover regulation of proximal or distal gene targets. Such variants with transcriptomic regulatory activity are termed expression quantitative trait loci (eQTLs). As transcriptomic regulation is context-dependent, eQTLs capture genetically and environmentally regulated expression, making them useful for deciphering genomic regulation of PTSD. I performed a preliminary eQTL search in post-mortem brain samples from the dorsolateral pre-frontal cortex (DLPFC), demonstrating that stress-interactive eQTLs are detectable in brains of trauma-exposed cohorts. In Aim 1, I will extend this analysis beyond the DLPFC to the medial amygdala, to uncover the regulatory landscape of genetic stress response across the brain. In Aim 2, I will examine causality of these variants to demonstrate stress-dependent regulation. I have developed an in vitro model capturing PTSD-specific stress response. In this model, candidate effector variants will be interrogated for downstream effects impacting disorder biology. This will be accomplished via training in large scale CRISPR-screening methods and in computational probing of convergent downstream pathways. This work will take place within the Icahn School of Medicine at Mount Sinai (ISMMS) and Yale University, currently ranked #11 and #10 among the nation’s best medical schools for research, respectively. Between the Departments of Genetics and Neuroscience, I am supported by over 100,000 ft2 of research programs and 4500 ft2 of institutional core facilities, in addition to over $200 million in scientific computing resources. Together, this fellowship leverages the resources of my institutional and the expertise of my co- sponsors to support my training in four major areas: (1) Scientific excellence, (2) professional development and scholarship, (3) mentorship, leadership, and advocacy, (4) and clinical-research integration.