Analysis of RORA and other candidate genes in PTSD

Va Boston Health Care System, Boston MA

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Abstract

DESCRIPTION (provided by applicant): Posttraumatic Stress Disorder (PTSD) is a psychiatric disorder characterized by profound disturbances in cognitive, behavioral and physiological functioning that occurs following exposure to a psychologically traumatic event. After exposure, the probability of developing PTSD is estimated to be approximately 10% in the general population, although higher rates (i.e., closer to 25%) have been observed among combat Veterans. Numerous factors contribute to the probability of developing the disorder including heredity. Twin studies have shown that a 30-70% of variation in PTSD risk is explained by genetic factors. In a recent paper (Logue et al, 2012); we reported results from the first published genome-wide association study (GWAS) for PTSD. We found that single nucleotide polymorphisms (SNPs) in the retinoid-related orphan receptor alpha (RORA) gene showed genome-wide significant associations with PTSD suggesting that this gene is an important risk locus for the disorder. RORA has been implicated in prior psychiatric GWAS as a risk factor for attention-deficit hyperactivity disorder, bipolar disorder, autism, and depression. The gene is also known to influence circadian rhythms, hormone regulation, and neuroprotection. Based on this, we believe that our finding implicating RORA in the development PTSD may point to a new and potentially important avenue for future research on the disorder. Therefore, the aim of the proposal is to conduct a more detailed genetic analysis of RORA and PTSD. Specifically, we propose to conduct extensive sequencing of RORA (along with several other PTSD candidate genes) to identify the complete array of genetic variation in these genes associated with PTSD risk and then perform genome- wide expression analysis using blood lymphocyte RNA. We also aim to follow-up our GWAS finding with analysis of additional PTSD-related comorbidity phenotypes and examination of possible gene-gene interactions. Findings are expected to shed new light on the role of RORA and other candidate genes on the development of PTSD.