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.
Posttraumatic stress disorder is a serious and potentially disabling condition that affects as many as 20% of US military Veterans during their lifetime. Recently, our research group conducted a genome-wide association study (GWAS) of PTSD and found that a gene called retinoid-related orphan receptor alpha (RORA) reliably discriminated individuals with PTSD from those who had been exposed to similar traumas but did not develop the disorder. RORA has been implicated previously as a risk factor for other psychiatric conditions and the protein produced by it is known to play a role in protecting brain cells from the biochemical effects of stress. In this project, we propose to follow-up our RORA discovery through additional molecular genetic studies (gene sequencing and expression studies) aimed at identifying the specific variant(s) most closely associated with PTSD and clarifying the molecular processes involved.
|Connolly, Samantha L; Stoop, Tawni B; Logue, Mark W et al. (2018) Posttraumatic Stress Disorder Symptoms, Temperament, and the Pathway to Cellular Senescence. J Trauma Stress 31:676-686|
|Duncan, L E; Ratanatharathorn, A; Aiello, A E et al. (2018) Largest GWAS of PTSD (N=20?070) yields genetic overlap with schizophrenia and sex differences in heritability. Mol Psychiatry 23:666-673|
|Wolf, Erika J; Maniates, Hannah; Nugent, Nicole et al. (2018) Traumatic stress and accelerated DNA methylation age: A meta-analysis. Psychoneuroendocrinology 92:123-134|
|Wolf, Erika J; Logue, Mark W; Stoop, Tawni B et al. (2017) Accelerated DNA Methylation Age: Associations with PTSD and Mortality. Psychosom Med :|
|Ratanatharathorn, Andrew; Boks, Marco P; Maihofer, Adam X et al. (2017) Epigenome-wide association of PTSD from heterogeneous cohorts with a common multi-site analysis pipeline. Am J Med Genet B Neuropsychiatr Genet 174:619-630|
|Sadeh, Naomi; Wolf, Erika J; Logue, Mark W et al. (2016) Polygenic Risk for Externalizing Psychopathology and Executive Dysfunction in Trauma-Exposed Veterans. Clin Psychol Sci 4:545-558|
|Sadeh, Naomi; Wolf, Erika J; Logue, Mark W et al. (2016) EPIGENETIC VARIATION AT SKA2 PREDICTS SUICIDE PHENOTYPES AND INTERNALIZING PSYCHOPATHOLOGY. Depress Anxiety 33:308-15|
|Logue, Mark W; Amstadter, Ananda B; Baker, Dewleen G et al. (2015) The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration. Neuropsychopharmacology 40:2287-97|
|Logue, Mark W; Smith, Alicia K; Baldwin, Clinton et al. (2015) An analysis of gene expression in PTSD implicates genes involved in the glucocorticoid receptor pathway and neural responses to stress. Psychoneuroendocrinology 57:1-13|
|Wolf, Erika J; Rasmusson, Ann M; Mitchell, Karen S et al. (2014) A genome-wide association study of clinical symptoms of dissociation in a trauma-exposed sample. Depress Anxiety 31:352-60|
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