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As Schizophrenia (SCZ) is the outcome of gene-gene-environmental interactions, there are possibly different pathophysiological mechanisms in different SCZ subtypes based on the risk factors. This study was aimed to examine the impacts of one of the most likely interactions, i.e. “dopamine and stress”, in SCZ pathogenesis. Here, we investigated the interaction between “War Trauma”, without brain trauma, and Catechol-O-Methyltransferase (COMT) gene expression. Using real-time PCR analysis we measured COMT gene expression level in the blood cells of 66 subjects in four groups, namely veteran SCZ patients as “stress-exposed SCZ” (S-SCZ), their healthy brothers as “their genetically closest relatives” (S-Siblings), SCZ patients without any history of significant stress as “Non-stress-exposed SCZ” (NoS-SCZ), and the control group. The COMT gene expression was different between the S-SCZ and NoS-SCZ groups, but not at statistically significant level; However, the COMT expression level was significantly decreased in three groups of S-SCZ, their healthy siblings, and NoS-SCZ groups compared to the control group. This data supports that the reduced blood COMT expression which is associated with higher dopamine level is involved both in stress-induced and non-stress induced SCZ.
Gene expression, Environment, Dopamine, War trauma, Blood.
Schizophrenia (SCZ) is a complex mental disorder that affects 0.5% to 1% of general population (Owen et al., 2016; Sadock and Ruiz, 2015; Simeone et al., 2015). Annually, almost 1 to 1.5 individuals per 10,000 are affected by this major mental disorder (Owen et al., 2016). SCZ is the third cause of disability, has imposed a large economic load on the western communities (Sadock and Ruiz, 2015), and it is more prevalent in developing countries (Brown, 2011).
SCZ encompasses a large number of environmental risk factors, such as maternal toxins and radiation exposure, maternal malnutrition, maternal infection, maternal stress, paternal age (above 40 years), maternal obstetrics and delivery complications, birth season, social rejection, immigration, adversity, drug abuse, and growth in densely populated or urban areas (Janoutova et al., 2016; Owen et al., 2016). In general, liability to SCZ is estimated to be impacted by environmental risk factors from 11% (Sullivan et al., 2003) to approximately 50% (Uher and Zwicker, 2017). On the other hand, in some studies, the involvement of hereditary factors in the development of SCZ has been reported to be from 60% to 80% (Cardno and Gottesman, 2000; Purcell et al., 2009); However, these risk ratios have been reported to be smaller in other studies (van Os and Sham, 2003; Zuk et al., 2012). Genetic research has found more than 100 chromosomal loci (Schizophrenia Working Group of the Psychiatric Genomics, 2014) and 2000 genes to be correlated to the disorder, but each one has a small effect size (Petronis, 2004). Overall, cumulative effects of genetic and environmental risk factors have been traced in the SCZ pathogenesis (Petronis, 2004).
Psychological stress is considered as the main underlying element in the majority of the environmental risk factors. It has been shown that ordinary stressors have more severe negative emotional effects on SCZ patients (Van Winkel et al., 2008b). In fact, there are many common genetic and environmental risk factors which dysregulate hypothalamic–pituitary–adrenal (HPA) axis and have roles in SCZ pathogenesis (Van Winkel et al., 2008b). There are some pathophysiological changes in the key elements of “stress response system” during the development of SCZ (Borges et al., 2013; Holtzman et al., 2013; Pruessner et al., 2017; Walker et al., 2008). For example, gene expression of glucocorticoid receptor (GR) decreases in the limbic areas (Perlman et al., 2004; Webster et al., 2002; Xing et al., 2004) leading to exaggeration and elongation of stress responses (Phillips et al., 2006). As GR is expressed in the dopaminergic and dopaminoceptive circuitry (Corcoran et al., 2003), stress sensitization induced by glucocorticoids dysregulation may trigger a cascade of events that ultimately lead to the dysregulation of dopaminergic system (Mizrahi et al., 2018).
Catechol-O-Methyltransferase (COMT) is one of the main players in the functionality of dopaminergic system (Abdolmaleky et al., 2005; Howes et al., 2017). There are several research findings addressing altered COMT expression in different diseases like SCZ (Abdolmaleky et al., 2006; Matsumoto et al., 2003b; Misiak et al., 2018; Tunbridge et al., 2004b) and Attention Deficit Hyperactivity Disorder (ADHD) (Faraone et al., 2014). Because of the scarcity of dopamine transporter in the frontal lobe, COMT is the main modulator of dopamine catabolism in this brain region (Wang et al., 1995). It has been proposed that, COMT hyperactivity and the resultant enhancement of dopamine degradation in the frontal cortex is associated with disturbances in attention, executive cognition, and working memory performance in both controls and SCZ patients (Blasi et al., 2005; Bruder et al., 2005; Egan et al., 2001; Frias et al., 2005) that may be progressive over time (Frias et al., 2005). Furthermore, COMT inhibitors may potentiate clozapine-induced dopamine release and improve prefrontal cortex performance (Tunbridge et al., 2004a).
COMT gene has two main isoforms with separate promoters: Membrane-Bound COMT (MB-COMT) and Soluble COMT (S-COMT) (Tenhunen et al., 1994). MB-COMT is important in SCZ pathogenesis as it is the predominant modulator of synaptic dopamine in the human brain (Matsumoto et al., 2003a; Tenhunen et al., 1994), which is up-regulated in SCZ (Nohesara et al., 2011). There are several polymorphisms in this gene, such as Val158Met (Chen et al., 2004). The Val158Met alleles code the enzymes with different levels of physiological activities (Lachman et al., 1996). In addition, these alleles are involved differently in attention (Blasi et al., 2005), cognition (Bruder et al., 2005; Egan et al., 2001), emotion (Kempton et al., 2009), reaction time (Stefanis et al., 2005), temperament resilience (Kang et al., 2013), novelty seeking personality traits (Montag et al., 2012; Wingo et al., 2016), harm avoidance (Enoch et al., 2003), SCZ (Glatt et al., 2003; Kunugi et al., 1997; Shifman et al., 2004), and stress susceptibility in healthy individuals (Abdolmaleky et al., 2006; Simons et al., 2009; Stefanis et al., 2007) and psychotic subjects (Collip et al., 2011; Modinos et al., 2013; van Winkel et al., 2008a). Also, it has been reported that a decrease in COMT level attenuates stress response in short-term, but increases stress susceptibility in the long term (Desbonnet et al., 2012).
As SCZ is the outcome of gene-gene-environmental interactions (Uher and Zwicker, 2017), there would be many combinations of genes and environmental risk factors that may result in diverse subtypes of SCZ with different therapeutic remedies (Keshavan et al., 2017). Here, we examined one of the most likely gene-environmental interactions, i.e. “dopamine and stress”, to clarify their roles in stress induced versus other SCZ patients. While stress is the core of majority of environmental risk factors, “War Trauma” is a specific type of extreme stress that is not only perceived as a potential life threatening physical stress for own self, but also a major psychological stress related to the injury or death of other combatants.
In this study, the COMT gene expression was measured in the peripheral blood cells of four groups, including 1) veterans diagnosed with SCZ following the exposure to Iraq-Iran war as “stress-exposed SCZ” (S-SCZ), 2) their healthy brothers as “their genetically closest relatives” (S-Siblings), 3) SCZ patients with no history of significant stress as the “non-stress exposed SCZ” (NoS-SCZ), and 4) the control subjects. Here we examined the expression of COMT in blood cells, as a peripheral biomarker that may represent the brain’s abnormalities of COMT gene expression (Luykx et al., 2016). The non-affected siblings of S-SCZ were included to investigate whether a potential COMT expression alteration in S-SCZ is a familial trait that may predispose individuals to SCZ, secondary to the war trauma, and/or antipsychotic drugs. We also included NoS-SCZ patients to investigate if potential alteration is specific to the stress induced SCZ or disease susceptibility, in general.
Based on the results of other studies, we estimated that the number of 15 cases in each group is needed to provide a statistic power of 0.8. For the omission of the monthly hormonal fluctuation effect, only male subjects were included. The subjects were a total 66 male individuals in the 35-to-63-year-oldage range (Mean= 49.56, Standard Deviation= 4.92). The Research Ethics Committee of Tehran University of Medical Sciences approved this case-control study.
The general exclusion criteria for all the groups, based on the participants’ medical charts that were also confirmed by the patients and their families, were as follows: epilepsy, loss of consciousness, drug abuse, chemical weapon injury, previous history of significant head trauma and brain injury (traumatic loss of consciousness, memory disturbance or convulsion), any neurological disease, and past and family history of mental retardation. Diabetes mellitus, hypertension, hyperlipidemia, minor thalassemia or mild iron deficiency anemia, cigarette smoking, and history of treatment with Electroconvulsive Therapy (ECT) were not considered as the exclusion criteria due to their high prevalence in the middle age or in SCZ patients. However, as shown in Table 1, the majority of these confounding factors existed in all study groups almost equally. In addition to the general exclusion criteria for all groups, thyroid diseases, familial (up to their third relatives) history of psychiatric disorder were considered as the exclusion criteria for the S-SCZ group. The exclusion criteria of the NoS-SCZ group were also similar to those of the S-SCZ group except that they had no war trauma experience, plus the negative familial history of mental disorders was not considered as an exclusion criterion in this group.
In order to choose the patients for S-SCZ group, the hospital charts of 400 admitted or observed veterans of Iraq-Iran war were assessed. They were continuously evaluated in Niayesh, Sadr, and Jannat hospitals. Among them, 150 cases were diagnosed as SCZ by psychiatrists and had a psychologically healthy male sibling (brother) at the similar age group. Also these cases had exhibited the disease symptoms during the first year after experiencing the war trauma. Based on Rahe’s psychological stress criteria, the onset of symptoms in a stress-induced disease must be manifested in less than one year after the incidence of stress (Spurgeon et al., 2001). Finally, a total of 17 cases were found eligible for participation in S-SCZ group in line with the required criteria of the study.
The second group consisted of the psychologically healthy male siblings of the S-SCZ group with similar environmental backgrounds but no experience of war trauma.
The cases for NoS-SCZ group were chosen from the SCZ patients who had been admitted to Roozbeh hospital (Tehran, Iran). Out of 200 male SCZ patients with an age of40-to-60-years, 16 cases were recognized eligible regarding the NoS-SCZ group criteria.
The subjects of the control group were 16 healthy males of Roozbeh hospital personnel, as introduced by the Health Department of the hospital and agreed to participate in this study. They were required to have no general exclusion criteria, no war trauma experience, and no psychiatric family history up to their third degree relatives.
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