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Nitric Oxide Pathway Genes (NOS1AP and NOS1) Are Involved in PTSD Severity, Depression, Anxiety, Stress and Resilience

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Nitric Oxide Pathway Genes (NOS1AP and NOS1) Are Involved in PTSD Severity, Depression, Anxiety, Stress and Resilience Please do not remove this page Nitric oxide pathway genes (NOS1AP and NOS1) are involved in PTSD severity, depression, anxiety, stress and resilience Bruenig, Dagmar; Morris, Charles P; Mehta, Divya; et.al. https://research.usc.edu.au/discovery/delivery/61USC_INST:ResearchRepository/12150219300002621?l#13151196550002621 Bruenig, D., Morris, C. P., Mehta, D., Harvey, W., Lawford, B., Young, R., & Voisey, J. (2017). Nitric oxide pathway genes (NOS1AP and NOS1) are involved in PTSD severity, depression, anxiety, stress and resilience. Gene, 625, 42–48. https://doi.org/10.1016/j.gene.2017.04.048 Document Type: Accepted Version Link to Published Version: https://doi.org/10.1016/j.gene.2017.04.048 USC Research Bank: https://research.usc.edu.au [email protected] CC BY-NC-ND V4.0 Copyright © 2017. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/ Downloaded On 2021/09/28 07:36:42 +1000 Please do not remove this page 1 Nitric oxide pathway genes (NOS1AP and NOS1) are involved in PTSD severity, depression, anxiety, stress and resilience Dagmar Bruenig1,2, Charles P. Morris1, Divya Mehta1, Wendy Harvey2, Bruce Lawford1, Ross McD Young1, Joanne Voisey1* 1 Institute of Health and Biomedical Innovation (IHBI) and School of Biomedical Sciences 60 Musk Avenue Queensland University of Technology Kelvin Grove, Queensland, 4059 Australia 2 Gallipoli Medical Research Institute, Greenslopes Private Hospital, Newdegate Street, Greenslopes QLD 4120 *Corresponding author Joanne Voisey School of Biomedical Sciences Faculty of Health Institute of Health and Biomedical Innovation (IHBI) 60 Musk Avenue Queensland University of Technology Kelvin Grove, Queensland, 4059 Australia Email: [email protected] 2 Phone: +61 7 3138 6261 Fax. +61 7 3138 6030 3 Abstract The nitric oxide pathway in the hippocampus is involved in the biological stress response with detrimental consequences to cells and HPA axis feedback. Hippocampal atrophy and HPA axis feedback dysfunction are associated with posttraumatic stress disorder (PTSD). This study systematically investigates two genes of the nitric oxide pathway NOS1AP and NOS1 for a potential involvement in PTSD, comorbidities and resilience. A cohort of age and gender matched Vietnam veterans including trauma-exposed cases and controls was recruited and comprehensively assessed (n = 299). A total of 49 NOS1AP and 16 NOS1 polymorphisms were analysed and genotypes correlated with gold standard clinical measures to assess PTSD severity and related phenotypes (depression, anxiety, stress, resilience) based on diagnostic status. Multiple NOS1AP polymorphisms were associated across all measures, and NOS1 polymorphisms were associated with PTSD severity, stress and resilience. The GG genotype of NOS1 polymorphism rs10744891 was associated with PTSD severity (surviving multiple correction) while the combined TT-TG genotypes were associated with resilience (p = 0.005; p = 0.033, respectively). This study indicates that NOS1AP and NOS1 from the nitric oxide pathway are likely to play a key role in PTSD, its comorbidities and resilience. Given the essential role of NOS1AP and NOS1 in stress response they may be reliable targets for screening and intervention strategies. Key Words: PTSD, depression, anxiety, resilience, NOS1AP, NOS1 4 Highlights • Association of NOS1AP and NOS1 with PTSD, comorbidities and resilience (coping) was tested • A well-screened cohort of combat exposed cases and controls was utilised • Association between NOS1AP and PTSD severity, depression, anxiety, and stress was found • Association between NOS1 and PTSD severity and stress was found • NOS1AP and NOS1 were both associated with resilience 5 1. Introduction Posttraumatic stress disorder (PTSD) is a severe psychiatric disorder that some individuals may develop following from the experience of a traumatic event (American Psychiatric Association, 2013). Despite similar traumatic exposure only a small portion of the population develops PTSD while the majority will show no clinically relevant symptoms (Schmidt et al., 2013). There is a strong genetic component to PTSD with the heritability generally reported to be about 40% (Lyons et al., 1993; Sartor et al., 2012). The molecular aetiology of PTSD is still poorly understood. The biological stress system (hypothalamic pituitary-adrenal axis; HPA axis) and genes of that pathway have typically been the focus of investigations into the aetiology of the disorder due to its centrality in the stress response. The activation of the stress cascade initiates processes within the HPA axis and in adjacent systems, often with detrimental effect. The nitric oxide pathway is directly linked with the HPA axis and has been hypothesised to play an integral role in development of PTSD (Freudenberg et al., 2015). Hippocampal atrophy is often observed in individuals with PTSD (Smith, 2005), and HPA feedback dysfunction is thought to be at the centre of the disorder due to a dysregulation of glucocorticoids (Yehuda, 2006). The nitric oxide pathway may contribute to these symptoms as nitric oxide impacts on gamma-aminobutyric acid (GABA) and glutamate levels. Furthermore, recent research indicates that there might be a direct link between nitric oxide synthase 1 (NOS1) and glucocorticoid regulation (Chen et al., 2015). Two key genes in the nitric oxide pathway are of interest in mental health research. The nitric oxide synthase 1 adaptor protein gene (NOS1AP; previously known as carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase protein gene: CAPON) produces an adaptor protein that binds to the enzyme NOS1 (encoded by the nitric oxide synthase 1 gene, NOS1), and influences n-methyl-d-aspartate (NMDA) receptor activity. Changes in receptor activity 6 have been associated with modulation of nitric oxide production. Increased nitric oxide causes a decrease in overall GABA level leading to HPA axis feedback dysfunction and an increase in glutamate causing excito-toxicity in the hippocampus (for a review, see (Chen et al., 2015) and (Wang et al., 2016)). A simplified schematic of the nitric oxide pathway including two of the key genes in connection with the HPA axis is shown in Figure 1. 7 Figure 1: A simplified schematic of the relationship between the HPA-Axis and the nitric oxide pathway including two key genes (NOS1AP and NOS1) Figure Legend: Triggering of the HPA axis initiates nitric oxide synthase 1 (NOS1) production. NOS1 is encoded by the NOS1 gene. Nitric oxide synthase 1 adaptor protein encoded by the NOS1AP gene binds with NOS1 and mediates N-methyl-D-aspartate (NMDA) receptor availability. Increased NOS1 activity down-regulates NMDA receptors and increases nitric oxide. Nitric oxide is known to lower GABA levels causing increased glutamate levels. Low GABA levels are associated with HPA axis feedback dysfunction and adrenal stress. Increased glutamate levels can cause cell burnout (excito-toxicity) leading to hippocampal atrophy as observed in PTSD patients (Chen et al., 2015; Freudenberg et al., 2015; Wang et al., 2016). 8 NOS1AP has been studied in a range of psychiatric disorders, including schizophrenia (Brzustowicz et al., 2004), autism spectrum disorder and obsessive-compulsive disorder (Delorme et al., 2010). Associations of NOS1AP variants with depression have previously been found in a cohort with schizophrenia (Cheah et al., 2015) and also with PTSD severity in a cohort of untreated combat veterans (Lawford et al., 2013). For NOS1, associations have been found with anxiety and depression in healthy cohorts (Harro et al., 2010; Kurrikoff et al., 2012) and a large general population sample (Sarginson et al., 2014). A genome-wide association study of personality traits and psychological distress established an effect of NOS1 on psychological distress (Luciano et al., 2012). The systematic investigation of the genetics of resilience and coping is still in the early phases (Dunn and Conley, 2015). A few genes have been identified to potentially play a role in resilience and coping, such as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 gene (SLC64A) and the dopamine receptor D2 gene (DRD2), (Wilhelm et al., 2007; van der Zwaluw et al., 2011), the beta-2 adrenergic receptor gene (ADRB2) (Poole et al., 2006; Liberzon et al., 2014), and the brain-derived neurotrophic factor gene (BDNF) (Caldwell et al., 2013). Some of these studies identified genetic association with maladaptive coping strategies, indicating a risk rather than a protective factor (van der Zwaluw et al., 2011). The finding of associations between NOS1 and neuroticism, which is commonly associated with maladaptive coping behaviour (Luciano et al., 2012), further support the role of NOS1 in poor coping outcomes. Research into another PTSD candidate gene BDNF indicates that the Val allele of the rs6265 (Val66Met) single nucleotide polymorphism (SNP) may have protective properties whereas the Met allele may be the risk factor for the disorder (Jiang et al., 2005; Bruenig et al., 2016). 9 Due to an increased body of research suggesting involvement of the nitric oxide pathway in mental health, it would be beneficial to understand any protective factors that may derive from genes of the nitric oxide pathway. Such genetic factors may contribute to enhanced homeostasis from the biological stress reaction and allow for more effective recovery from extreme stress. Understanding the role of genes in resilience and coping may lead
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