Integration of multi-omic data and biological validation for gene prioritization in PTSD risk loci

A major hurdle in the study of posttraumatic stress disorder (PTSD) is the determination of the biological factors that influence the development of PTSD. It has been established that genetic factors underlie PTSD biology. Thus, to gain insights into this biology, extensive efforts have been placed on identifying genetic variation that confers risk for PTSD development. Replicable genetic risk loci have only recently emerged from very large genomic studies of PTSD, i.e. genome-wide association studies. However, there is limited understanding of exactly how the implicated risk loci act to influence PTSD development, as there is a considerable biological distance between risk loci and PTSD. Additional insights into the effects of the genome on PTSD are being provided by studies of the molecular mediators of genetic risk, including studies of epigenetic modification, as these form the bridge between genetic risk and PTSD. In addition, recently experimental studies of human induced pluripotent stem cell (iPSC) neurons have been conducted in an effort to link the genome to the neurobiological mechanisms thought to directly underlie PTSD. Now, increasingly, calls are being made to integrate these various study types in ways that will enhance power to deliver novel biological insights. With this in mind, the present study proposes to integrate various “omics” - the genome, epigenome, phenome, and transcriptome - using data available from the Million Veteran Program, in conjunction with iPSC experimental models in human neurons, to provide an in-depth examination into the biological mediation of genetic risk variation that influences the development of PTSD and its sequelae in Veterans. Strengths of this proposal include (1) the integration of large-scale omic data resources, (2) a focus on PTSD and comorbidities specifically in Veteran populations, and (3) human specific experimental models of PTSD. Findings from this study will reduce the existing knowledge gaps of how genetic variation influences PTSD risk, and this information may have particular relevance to treatments currently being developed and optimized within a precision medicine approach to target those most at risk of poor outcomes. The applicant is currently a Research Health Science Specialist at the VA San Diego Healthcare System. Successful completion of this VA Career Development Award-2 (CDA-2) will allow the candidate to advance toward a long-term career goal of being an independent research scientist within the VA, focused on the development of a PTSD research program that serves to elucidate the genetic underpinnings of PTSD by incorporating big data, integrative genomic studies, and experimental cellular models, in order to clarify the processes that link the genome to PTSD risk and resilience. To successfully develop an independent research program, the candidate would benefit from the additional training and experience that this CDA-2 would provide. Specific training goals are to: (1) acquire competencies in the derivation and extraction of clinically relevant phenotype data from large electronic health record data, (2) learn how to integrate genomics with other forms of omic data to bridge the knowledge gap between risk variation and PTSD, (3) learn how to conduct experimental molecular investigations of PTSD, and (4) obtain mentorship related to scientific and professional development. Working collaboratively with a distinguished mentorship team, the candidate will receive the necessary training and preparation that will allow for advancement toward independence as a research scientist within the VA.