Computational Biology - Publications

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Browsing Computational Biology - Publications by Author "Abu-Amara, Duna"
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    Effect of Combat Exposure and Posttraumatic Stress Disorder on Telomere Length and Amygdala Volume
    ( 2020-07-01) Kang, Jee In ; Mueller, Susanne G. ; Wu, Gwyneth W.Y. ; Lin, Jue ; Ng, Peter ; Yehuda, Rachel ; Flory, Janine D. ; Abu-Amara, Duna ; Reus, Victor I. ; Gautam, Aarti ; Hood, Leroy ; Ressler, Kerry J. ; Lindqvist, Daniel ; Cho, Ji Hoon ; Coy, Michelle ; Desarnaud, Frank ; Bersani, Saverio ; Fossati, Silvia ; Hoke, Allison ; Kumar, Raina ; Li, Meng ; Makotkine, Iouri ; Miller, Stacy Ann ; Petzold, Linda ; Price, Laura ; Qian, Meng ; Scherler, Kelsey ; Srinivasan, Seshamalini ; Suessbrick, Anna ; Tang, Li ; Wu, Xiaogang ; Baxter, David ; Blessing, Esther ; Dean, Kelsey R. ; Daigle, Bernie J. ; Guffanti, Guia ; Wang, Kai ; Almli, Lynn M. ; Chakraborty, F. Nabarun ; Donohue, Duncan ; Kerley, Kimberly ; Kim, Taek Kyun ; Laska, Eugene ; Lee, Inyoul ; Lee, Min Young ; Lori, Adriana ; Lu, Liangqun ; Misganaw, Burook ; Muhie, Seid ; Newman, Jennifer ; Price, Nathan ; Qin, Shizhen ; Siegel, Carole ; Somvanshi, Pramod R. ; Thakur, Gunjan S. ; Zhou, Young ; Yang, Ruoting ; Hammamieh, Rasha ; Doyle, Francis J. ; Jett, Marti ; Marmar, Charles R. ; Mellon, Synthia H. ; Wolkowitz, Owen M.
    Background: Traumatic stress can adversely affect physical and mental health through neurobiological stress response systems. We examined the effects of trauma exposure and posttraumatic stress disorder (PTSD) on telomere length, a biomarker of cellular aging, and volume of the amygdala, a key structure of stress regulation, in combat-exposed veterans. In addition, the relationships of psychopathological symptoms and autonomic function with telomere length and amygdala volume were examined. Methods: Male combat veterans were categorized as having PTSD diagnosis (n = 102) or no lifetime PTSD diagnosis (n = 111) based on the Clinician-Administered PTSD Scale. Subjects were assessed for stress-related psychopathology, trauma severity, autonomic function, and amygdala volumes by magnetic resonance imaging. Results: A significant interaction was found between trauma severity and PTSD status for telomere length and amygdala volume after adjusting for multiple confounders. Subjects with PTSD showed shorter telomere length and larger amygdala volume than those without PTSD among veterans exposed to high trauma, while there was no significant group difference in these parameters among those exposed to low trauma. Among veterans exposed to high trauma, greater telomere shortening was significantly correlated with greater norepinephrine, and larger amygdala volume was correlated with more severe psychological symptoms and higher heart rates. Conclusions: These data suggest that the intensity of the index trauma event plays an important role in interacting with PTSD symptomatology and autonomic activity in predicting telomere length and amygdala volume. These results highlight the importance of trauma severity and PTSD status in predicting certain biological outcomes.
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    Mechanistic inferences on metabolic dysfunction in posttraumatic stress disorder from an integrated model and multiomic analysis: Role of glucocorticoid receptor sensitivity
    ( 2019-11-01) Somvanshi, Pramod R. ; Mellon, Synthia H. ; Flory, Janine D. ; Abu-Amara, Duna ; Wolkowitz, Owen M. ; Yehuda, Rachel ; Jett, Marti ; Hood, Leroy ; Marmar, Charles ; Doyle, Francis J.
    Posttraumatic stress disorder (PTSD) is associated with neuroendocrine alterations and metabolic abnormalities; however, how metabolism is affected by neuroendocrine disturbances is unclear. The data from combat-exposed veterans with PTSD show increased glycolysis to lactate flux, reduced TCA cycle flux, impaired amino acid and lipid metabolism, insulin resistance, inflammation, and hypersensitive hypothalamic-pituitary-adrenal (HPA) axis. To analyze whether the co-occurrence of multiple metabolic abnormalities is independent or arises from an underlying regulatory defect, we employed a systems biological approach using an integrated mathematical model and multiomic analysis. The models for hepatic metabolism, HPA axis, inflammation, and regulatory signaling were integrated to perform metabolic control analysis (MCA) with respect to the observations from our clinical data. We combined the metabolomics, neuroendocrine, clinical laboratory, and cytokine data from combat-exposed veterans with and without PTSD to characterize the differences in regulatory effects. MCA revealed mechanistic association of the HPA axis and inflammation with metabolic dysfunction consistent with PTSD. This was supported by the data using correlational and causal analysis that revealed significant associations between cortisol suppression, high-sensitivity C-reactive protein, homeostatic model assessment of insulin resistance, γ-glutamyltransferase, hypoxanthine, and several metabolites. Causal mediation analysis indicates that the effects of enhanced glucocorticoid receptor sensitivity (GRS) on glycolytic pathway, gluconeogenic and branched-chain amino acids, triglycerides, and hepatic function are jointly mediated by inflammation, insulin resistance, oxidative stress, and energy deficit. Our analysis suggests that the interventions to normalize GRS and inflammation may help to manage features of metabolic dysfunction in PTSD.
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    Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder
    ( 2020-12-01) Dean, Kelsey R. ; Hammamieh, Rasha ; Mellon, Synthia H. ; Abu-Amara, Duna ; Flory, Janine D. ; Guffanti, Guia ; Wang, Kai ; Daigle, Bernie J. ; Gautam, Aarti ; Lee, Inyoul ; Yang, Ruoting ; Almli, Lynn M. ; Bersani, F. Saverio ; Chakraborty, Nabarun ; Donohue, Duncan ; Kerley, Kimberly ; Kim, Taek Kyun ; Laska, Eugene ; Young Lee, Min ; Lindqvist, Daniel ; Lori, Adriana ; Lu, Liangqun ; Misganaw, Burook ; Muhie, Seid ; Newman, Jennifer ; Price, Nathan D. ; Qin, Shizhen ; Reus, Victor I. ; Siegel, Carole ; Somvanshi, Pramod R. ; Thakur, Gunjan S. ; Zhou, Yong ; Baxter, David ; Bierer, Linda ; Blessing, Esther ; Cho, Ji Hoon ; Coy, Michelle ; Desarnaud, Frank ; Fossati, Silvia ; Hoke, Allison ; Kumar, Raina ; Li, Meng ; Makotkine, Iouri ; Miller, Stacy Ann ; Petzold, Linda ; Price, Laura ; Qian, Meng ; Scherler, Kelsey ; Srinivasan, Seshamalini ; Suessbrick, Anna ; Tang, Li ; Wu, Xiaogang ; Wu, Gwyneth ; Wu, Changxin ; Hood, Leroy ; Ressler, Kerry J. ; Wolkowitz, Owen M. ; Yehuda, Rachel ; Jett, Marti ; Doyle, Francis J. ; Marmar, Charles
    Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.
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    Serum brain-derived neurotrophic factor remains elevated after long term follow-up of combat veterans with chronic post-traumatic stress disorder
    ( 2021-12-01) Wu, Gwyneth W.Y. ; Wolkowitz, Owen M. ; Reus, Victor I. ; Kang, Jee In ; Elnar, Mathea ; Sarwal, Reuben ; Flory, Janine D. ; Abu-Amara, Duna ; Hammamieh, Rasha ; Gautam, Aarti ; Doyle, Francis J. ; Yehuda, Rachel ; Marmar, Charles R. ; Jett, Marti ; Mellon, Synthia H. ; Ressler, Kerry J. ; Yang, Ruoting ; Muhie, Seid ; Daigle, Bernie J. ; Bierer, Linda M. ; Hood, Leroy ; Wang, Kai ; Lee, Inyoul ; Dean, Kelsey R. ; Somvanshi, Pramod R.
    Attempts to correlate blood levels of brain-derived neurotrophic factor (BDNF) with post-traumatic stress disorder (PTSD) have provided conflicting results. Some studies found a positive association between BDNF and PTSD diagnosis and symptom severity, while others found the association to be negative. The present study investigated whether serum levels of BDNF are different cross-sectionally between combat trauma-exposed veterans with and without PTSD, as well as whether longitudinal changes in serum BDNF differ as a function of PTSD diagnosis over time. We analyzed data of 270 combat trauma-exposed veterans (230 males, 40 females, average age: 33.29 ± 8.28 years) and found that, at the initial cross-sectional assessment (T0), which averaged 6 years after the initial exposure to combat trauma (SD = 2.83 years), the PTSD positive group had significantly higher serum BDNF levels than the PTSD negative controls [31.03 vs. 26.95 ng/mL, t(268) = 3.921, p < 0.001]. This difference remained significant after excluding individuals with comorbid major depressive disorder, antidepressant users and controlling for age, gender, race, BMI, and time since trauma. Fifty-nine of the male veterans who participated at the first timepoint (T0) were re-assessed at follow-up evaluation (T1), approximately 3 years (SD = 0.88 years) after T0. A one-way ANOVA comparing PTSD positive, “subthreshold PTSD” and control groups revealed that serum BDNF remained significantly higher in the PTSD positive group than the control group at T1 [30.05 vs 24.66 ng/mL, F(2, 56) = 3.420, p = 0.040]. Serum BDNF levels did not correlate with PTSD symptom severity at either time point within the PTSD group [r(128) = 0.062, p = 0.481 and r(28) = 0.157, p = 0.407]. Serum BDNF did not significantly change over time within subjects [t(56) = 1.269, p = 0.210] nor did the change of serum BDNF from T0 to T1 correlate with change in PTSD symptom severity within those who were diagnosed with PTSD at T0 [r(27) = −0.250, p = 0.192]. Our longitudinal data are the first to be reported in combat PTSD and suggest that higher serum BDNF levels may be a stable biological characteristic of chronic combat PTSD independent of symptom severity.