Article

Catechol-o-methyltransferase polymorphism and susceptibility to major depressive disorder modulates psychological stress response

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  • Dell Medical School, University of Texas at Austin
Article

Catechol-o-methyltransferase polymorphism and susceptibility to major depressive disorder modulates psychological stress response

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Abstract

The stress response is related to both physiological and psychological factors and is strongly marked by a neuroendocrine component. Genetic factors are believed to underlie individual differences in the degree of stress resilience and thereby contribute in determining susceptibility to stress-related pathologies like major depressive disorder (MDD). Little, however, is known about the genetic influence on the endocrine and behavioural stress response in relation to MDD. Here, we sought to examine the effects of the catechol-o-methyltransferase polymorphism on psychological stress in three groups of individuals with different degrees of susceptibility to MDD (i.e. healthy controls, healthy high risk probands to MDD and those suffering from MDD). This genotype is involved in the metabolism of catecholamines (dopamine, norepinephrine and epinephrine). Allelic variations of this polymorphism were found to influence the degree of subjective stress experience and plasma epinephrine stress response. Interactions between catechol-o-methyltransferase polymorphism and diagnostic group in measures of plasma epinephrine, cortisol and subjective responses to psychological stress were also found, with the influence of the different alleles on these measures differing between healthy controls relative to MDD patients and high risk probands. These observations support a possible role for catechol-o-methyltransferase polymorphism in the endocrine and subjective response to psychological stress and thus may qualify as a possible candidate gene involved in the pathogenesis of MDD.

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... A common functional polymorphism in COMT, which is the result of a G to A mutation (c.472G > A) that translates into a valine to methionine substitution at codon 158 (Val158Met), has been linked to a 3-4-fold decrease of the methylation activity of the enzyme [33], and also has been shown to account for a 40% decrease in enzyme activity in the human brain [34]. Studies have indicated that the Met 158 COMT allele influences pre-frontal cortex and limbic activity in response to aversive or emotionally-negative stimuli and to the endocrine response to stress [35,36]. A large number of evidence suggests that this polymorphism is associated with major depressive disorder (MDD) and bipolar depression [37][38][39][40][41][42][43][44][45] (Table 1). ...
... However, several case-control association studies of COMT alleles were negative [38,41,42] or distribution of the high activity Val 158 variant was significantly increased in MDD [43] (Table 1). Additionally, the involvement of this polymorphic variant may depend on the effects of stressful life events on depression [35,36] and this vulnerability has also been implicated in postpartum depressive symptoms (PPD) [26,37]. So far, however, no case-control studies have examined the association between COMT genotypes and depression in climacteric women and this is the first report on the occurrence of the c.472G > A polymorphism in Caucasian women with menopausal depression. ...
... However, when we compared the distribution of COMT c.472 GG, GA and AA genotypes in both groups, the GA and AA genotypes were associated with significantly higher risk of depression in postmenopausal women. This may be partly explained by the fact that the low activity COMT variant, which leads to altered dopaminergic regulation, may be associated with a worse response to life stressors that predispose to the development of depressive symptoms among menopausal women [35,36,82,83]. ...
Article
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Objective: The aim of the study was assessment of a possible relationship between the polymorphisms of the candidate genes participating in the etiology of some neurological and psychiatric disorders and the risk of depression in perimenopausal and postmenopausal women. Methods: A total of 167 (54 perimenopausal and 113 postmenopausal) Caucasian women from western Poland, aged 42-67, were recruited as the patient group in the study because of depressive symptoms, and another 321 healthy women (102 perimenopausal and 219 postmenopausal) served as the controls. All study participants were evaluated for climacteric and depressive disorders according to the Kupperman index and Hamilton rating scale for depression (HRSD), respectively. The following candidate genes were selected for the study: 5HTR2A, 5HTR1B, 5HTR2C, TPH1, TPH2, MAOA, COMT, NET, GABRB1, ESR1, MTHFR, MTR and MTHFD1. In each group the frequencies of the polymorphisms were determined using PCR-RFLP analysis. Results: After correcting for Bonferroni multiple tests, we found associations between the MAOA c.1460C>T (SNP 1137070), COMT c.472G>A (SNP 4680), MTHFR c.677C>T (SNP 1801133) and ESR1 454(-351) A>G (SNP 9340799) polymorphisms to mild and moderate depressive symptoms in menopausal women. In the perimenopausal and postmenopausal women, genotype association of the MAOA c.1460 CT and c.1460 CT+TT (OR=1.83; pcorr=0.009 and OR=1.85; pcorr=0.003, resp.), and of the MTHFR c.677 TT and c.677 CT+TT (OR=3.52; pcorr=0.00009 and OR=2.06; pcorr=0.0006, resp.), as well as of the COMT c.472 GA and COMT c.472 GA+AA genotypes (OR=2.23; pcorr=0.03 and OR=2.17; pcorr=0.027, resp.) in the postmenopausal women revealed significantly higher frequencies of these variants in depressed female patients than in controls, whereas the ESR1 454(-351) AG and 454(-351) AG+GG genotypes were associated with lower risk of depression in postmenopausal women (OR=0.48; pcorr=0.012, and OR=0.52; pcorr=0.015, resp.). Conclusions: Our study substantiates the involvement of the MAOA and MTHFR polymorphisms in climacteric depression and offers evidence that the COMT and ESR1 genes may also play a role in the susceptibility to depressive mood in postmenopausal women.
... The transcriptional activity of the 5-HTT gene is significantly modulated by a length polymorphism in its promoter region, (termed the gene-linked polymorphic region; 5-HTTLPR) which produces two allelic forms of 5-HTTLPR: the long (L) allele and the short (S) allele, which is associated with lower transcriptional efficiency than the L allele (Lesch et al., 1996). While the 5-HTTLPR genotype has been clearly associated with individual differences in HPA axis activity (Barr et al., 2004;Gotlib et al., 2008;Jabbi et al., 2007;Mueller et al., 2011), studies of its effect on autonomic stress reactivity have produced conflicting results depending on parameters used. While in L allele carriers higher HR responses have been found (Williams et al., 2001(Williams et al., , 2008 to a mental stressor, another study found blood pressure (BP) to be unrelated to 5-HTTLPR genotype and HR to be greater only in women homozygous for the S allele (McCaffery et al., 2003). ...
... This G to A mutation results in a substitution of valine by methionine at codon 158 (val 158 met) with the met allele showing a four-fold reduction and intermediate COMT activity in val/met allele carriers (Scanlon et al., 1979). These genetically determined differences in catecholamine metabolism likely influence the HPA axis (Dorn et al., 2003) as well as ANS function during stress with the COMT met allele being associated with greater subjective and HPA axis stress responses (Jabbi et al., 2007;Nater and Rohleder, 2009). In the two studies investigating the influence of COMT genotypes on ANS response to an acute psychosocial stressor, highest EPI stress and recovery values were found in adults with two met alleles (Jabbi et al., 2007). ...
... These genetically determined differences in catecholamine metabolism likely influence the HPA axis (Dorn et al., 2003) as well as ANS function during stress with the COMT met allele being associated with greater subjective and HPA axis stress responses (Jabbi et al., 2007;Nater and Rohleder, 2009). In the two studies investigating the influence of COMT genotypes on ANS response to an acute psychosocial stressor, highest EPI stress and recovery values were found in adults with two met alleles (Jabbi et al., 2007). Further, higher basal sAA levels were found in insecure infants with the val/val genotype (Frigerio et al., 2009). ...
Article
Identification of genetic factors that influence stress reactivity is important in order to link environmental demands, particularly adversity to disease outcome. There is ample literature on genetic contribution to the endocrine stress response, while evidence for genetic contribution to individual differences in autonomic nervous system function is sparse and produced conflicting results. Here, we investigated the influence of two polymorphisms in the Catechol-o-methyltransferase (COMT) and serotonin transporter (5-HTT; SCL6A4) gene. We examined the autonomic stress response to the Trier Social Stress Test for Children in 115 children. Salivary α-amylase (sAA) was obtained prior to the stressor and repeatedly during recovery as a marker of autonomic reactivity. Furthermore, heart rate (HR) and heart rate variability (HRV) were monitored continuously. We found differences in ANS stress response associated with each polymorphism (all p<.05). Children with the L variant of 5-HTTLPR showed a higher increase and sharper recovery of sAA in response to stress than those with S variants. For HR, we found differences associated with COMT, i.e. children carrying at least one met allele showed lower mean HR increase and slower HR recovery in response to the stressor compared to those with two val alleles (p<.001) as well as a significant decrease in heart rate variability (p<.05). Our findings indicate that these two polymorphisms do indeed influence the ANS response to stress. This study provides further evidence for the crucial role of genetic factors in the modulation of differences in the acute stress response during childhood.
... is an enzyme involved in the degradation of catecholamines. It is encoded by the COMT gene (chromosome 22 band q11.2) that displays several allelic variants of which the functional single nucleotide polymorphismVal 158 Met is most studied [27,28]. This functional polymorphism in the COMT gene is the result of a G to A mutation that translates into a valine (val) to methionine (met) substitution at codon 158. ...
... The low-activity Met/ Met genotype has been associated with reduced COMT enzyme activity in the brain [29,32]. Low enzyme activity leads to an impaired endocrine response to stress [28]. It could thus be that, when experiencing stress, Met/Met carriers would show a more flattened CAR and DCS, as they are less able to degrade catecholamines, leading to lower HPA-axis reactivity and an impaired ability to regulate or degrade cortisol levels. ...
... They indicate that Met/Met carriers, compared to the other COMT variant carriers, may indeed have a relative insensitivity to modulating the endocrine stress reactivity, and a reduced capability to degrade cortisol secretion [30]. Previous research suggests that Met/Met carriers show inflexibility with adapting to changing situations and respond more inefficiently to worries with respect to their cortisol levels [28,58,59]. It could be suggested that only well after diagnosis, when permanent life changes are visible, the effect of COMT genotype becomes visible. ...
Article
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Due to physical hindrance and time spent in hospital, a cancer diagnosis can lead to disturbance of personally important goals. Goal disturbance in cancer patients has been related to poorer psychological well-being. However, the relation with physiological measures is yet unknown. The purpose of the current study is to examine the impact of goal disturbance on cortisol as a measure of response to stress over time, and a possibly moderating role of a DNA genotype associated with HPA-axis functioning, Catechol-O-Methyl transferase (COMT). We examined the predictive value of goal disturbance on Cortisol Awakening Response (CAR) and Diurnal Cortisol Slope (DCS) over two periods: 1-7 and 7-18 months post-diagnosis, and the moderating role of COMT during these periods. Hierarchical regression analyses showed that goal disturbance 7 months post-diagnosis significantly predicted a steeper CAR a year later. During that period, the slow COMT variant moderated the relation, in that patients reporting high goal disturbance and had the Met/Met variant, had a more flattened CAR. No other significant effects were found. As steeper CARs have been related to adverse health outcomes, and COMT genotype may modify this risk, these results indicate that goal disturbance and genotype may be important factors to consider in maintaining better psychological and physical health in the already vulnerable population of cancer patients.
... 作用机制。 既有研究表明, MAOA 基因是与抑郁紧密关联 的重要候选基因之一 (Dunn et al., 2011(Dunn et al., , 2015Roy et al., 2014) Jabbi et al., 2007;Papaleo et al., 2008), 亦更易卷入抑郁情绪 (Jabbi et al., 2007) (Gong et al., 2013;Larson et al., 2010), 亦有研究显示, COMT Met 等位基因与压力应激反应存在显著关联 (Jabbi et al., 2007;Papaleo et al., 2008); 而且, 该等位基 因 具 有 更 强 的 情 绪 敏 感 性 (Drabant et al., 2006;Gohier et al., 2014) ...
... 作用机制。 既有研究表明, MAOA 基因是与抑郁紧密关联 的重要候选基因之一 (Dunn et al., 2011(Dunn et al., , 2015Roy et al., 2014) Jabbi et al., 2007;Papaleo et al., 2008), 亦更易卷入抑郁情绪 (Jabbi et al., 2007) (Gong et al., 2013;Larson et al., 2010), 亦有研究显示, COMT Met 等位基因与压力应激反应存在显著关联 (Jabbi et al., 2007;Papaleo et al., 2008); 而且, 该等位基 因 具 有 更 强 的 情 绪 敏 感 性 (Drabant et al., 2006;Gohier et al., 2014) ...
... 作用机制。 既有研究表明, MAOA 基因是与抑郁紧密关联 的重要候选基因之一 (Dunn et al., 2011(Dunn et al., , 2015Roy et al., 2014) Jabbi et al., 2007;Papaleo et al., 2008), 亦更易卷入抑郁情绪 (Jabbi et al., 2007) (Gong et al., 2013;Larson et al., 2010), 亦有研究显示, COMT Met 等位基因与压力应激反应存在显著关联 (Jabbi et al., 2007;Papaleo et al., 2008); 而且, 该等位基 因 具 有 更 强 的 情 绪 敏 感 性 (Drabant et al., 2006;Gohier et al., 2014) ...
... In turn, stress has also been found to impact dopaminergic function (Arnsten & Goldman-Rakic, 1998 ;Murphy et al. 1996). Variations in the gene coding for catechol-O-methyltransferase (COMT), the enzyme facilitating metabolic degradation of catecholamines (Chen et al. 2004 ;Weinshilboum et al. 1999), have been suggested to impact stress reactivity (Jabbi et al. 2007 ;Zubieta et al. 2003). COMT exists in two isoforms : soluble, predominantly expressed in tissues such as liver, blood and kidney ; membrane-bound, mainly expressed in the brain, particularly in the PFC (Chen et al. 2004 ;Karoum et al. 1994 ;Matsumoto et al. 2003 ;Tenhunen et al. 1993). ...
... However, while there are numerous studies on emotional regulation, fewer studies have investigated the link between COMT and the stress response in general and HPA axis reactivity in particular. Recently, Jabbi et al. (2007) reported higher plasma epinephrine levels and elevated subjective stress ratings in response to a modified version of the Trier Social Stress Test (TSST) in COMT Met/Met homozygotes. Furthermore, an interaction effect between COMT Val 158 Met and a functional variable number of tandem repeats (VNTR) polymorphism in the dopamine transporter gene (DAT1 VNTR) -but no COMT main effect -was found in response to a public speaking paradigm in healthy young men (Alexander et al. 2011). ...
... Existing findings also mainly suggest the Met allele as a risk factor for deficits in stress responses. Met/Met homozygotes showed higher plasma epinephrine levels and higher subjective stress ratings after confrontation with a psychosocial stressor (Jabbi et al. 2007). Furthermore, an interaction effect has been reported between COMT Val 158 Met and DAT1 VNTR. ...
Article
Full-text available
Dopamine and norepinephrine are key regulators of cognitive and affective processes. The enzyme catechol-O-methyltransferase (COMT) catabolizes catecholamines and the COMT Val158Met polymorphism has been linked to several neuropsychiatric variables. Additionally, stressful life events (SLEs) contribute substantially to affective processes. We used the stress-induced activation of the hypothalamic-pituitary-adrenal axis to investigate the effects of COMT and SLEs on the cortisol response in 119 healthy children (8-12 yr). Saliva cortisol was measured during and after the Trier Social Stress Test for Children. SLEs were assessed with a standardized interview with one of the children's parents. Linear regression analysis revealed a significant effect for COMT, with Met allele carriers showing a higher cortisol response (β=0.300, p=0.001). In turn, more SLEs lead to a less pronounced cortisol increase (β=-0.192, p=0.029) probably indicating increased resilience. Our results further underscore the essential and differential role of genetic variation and environmental factors on stress responsivity.
... Meanwhile, as discussed above, the ethologically relevant mimicking of stress in animal models of depression may be crucial for translational research in this field, since stress can play a major role in the development of a depressive disorder. While depressive disorders are caused by a multi-factorial neuropsychiatric pathology where the occurrence of stress experiences does not necessarily result in clinical depression in an individual, sustained or repetitive stress was shown to increase its incidence in the population (Lesch, 2004;Vergne and Nemeroff, 2006;Jabbi et al., 2007;Maccari and Morley-Fletcher, 2007;Tsuji et al., 2014). Increased susceptibility of an individual to a stressinduced depressive state is viewed as a complex interplay between genetic and environmental factors that trigger maladaptive neurobiological changes (de Kloet et al., 2005;McEwen and Stellar, 1993;Jabbi et al., 2007;Jacobson and Cryan, 2007). ...
... While depressive disorders are caused by a multi-factorial neuropsychiatric pathology where the occurrence of stress experiences does not necessarily result in clinical depression in an individual, sustained or repetitive stress was shown to increase its incidence in the population (Lesch, 2004;Vergne and Nemeroff, 2006;Jabbi et al., 2007;Maccari and Morley-Fletcher, 2007;Tsuji et al., 2014). Increased susceptibility of an individual to a stressinduced depressive state is viewed as a complex interplay between genetic and environmental factors that trigger maladaptive neurobiological changes (de Kloet et al., 2005;McEwen and Stellar, 1993;Jabbi et al., 2007;Jacobson and Cryan, 2007). ...
Article
Emotional stress is primarily triggered by the cognitive processing of negative input; it is regarded as a serious pathogenetic factor of depression that is challenging to model in animals. While available stress paradigms achieve considerable face and construct validity in modelling depressive disorders, broader use of naturalistic stressors instead of the more prevalent models with artificial challenges inducing physical discomfort or pain may substantially contribute to the development of novel antidepressants. Here, we investigated whether a 3-week exposure of Wistar rats and Balb/c mice to unpredictably alternating frequencies of ultrasound between the ranges of 20-25 and 25-45kHz, which are known to correspond with an emotionally negative and with a neutral emotional state, respectively, for small rodents in nature, can induce behavioural and molecular depressive-like changes. Both rats and mice displayed decreased sucrose preference, elevated "despair" behaviour in a swim test, reduced locomotion and social exploration. Rats showed an increased expression of SERT and 5-HT2A receptor, a decreased expression of 5-HT1A receptor in the prefrontal cortex and hippocampus, diminished BDNF on gene and protein levels in the hippocampus. Fluoxetine, administered to rats at the dose of 10mg/kg, largely precluded behavioural depressive-like changes. Thus, the here applied paradigm of emotional stress is generating an experimental depressive state in rodents, which is not related to any physical stressors or pain. In essence, this ultrasound stress model, besides enhancing animal welfare, is likely to provide improved validity in the modelling of clinical depression and may help advance translational research and drug discovery for this disorder.
... Meanwhile, as discussed above, the ethologically relevant mimicking of stress in animal models of depression may be crucial for translational research in this field, since stress can play a major role in the development of a depressive disorder. While depressive disorders are caused by a multi-factorial neuropsychiatric pathology where the occurrence of stress experiences does not necessarily result in clinical depression in an individual, sustained or repetitive stress was shown to increase its incidence in the population (Lesch, 2004;Vergne and Nemeroff, 2006;Jabbi et al., 2007;Maccari and Morley-Fletcher, 2007;Tsuji et al., 2014). Increased susceptibility of an individual to a stressinduced depressive state is viewed as a complex interplay between genetic and environmental factors that trigger maladaptive neurobiological changes (de Kloet et al., 2005;McEwen and Stellar, 1993;Jabbi et al., 2007;Jacobson and Cryan, 2007). ...
... While depressive disorders are caused by a multi-factorial neuropsychiatric pathology where the occurrence of stress experiences does not necessarily result in clinical depression in an individual, sustained or repetitive stress was shown to increase its incidence in the population (Lesch, 2004;Vergne and Nemeroff, 2006;Jabbi et al., 2007;Maccari and Morley-Fletcher, 2007;Tsuji et al., 2014). Increased susceptibility of an individual to a stressinduced depressive state is viewed as a complex interplay between genetic and environmental factors that trigger maladaptive neurobiological changes (de Kloet et al., 2005;McEwen and Stellar, 1993;Jabbi et al., 2007;Jacobson and Cryan, 2007). ...
Research
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Manuscript about new approach in modeling of depressive-like behaviour in rat and mice
... Five studies investigated COMT polymorphisms, and all studies reported the Val allele as associated with resilience, reaching consensus (186, 204,215,217,229). Of the five studies, two studies were fMRI studies assessing the effects of COMT Val158Met genotype on emotional stimuli processing. ...
... They found the presence of a Val158 allele results in an increase in emotional resilience against negative mood states via decreased neuronal activation to unpleasant stimuli (215,217). Two studies used psychological measures; subjective stress experience (204), and sadness score (186), and one study assessed resilience via cortisol response levels (229). ...
Article
Full-text available
Resilience is broadly defined as the ability to maintain or regain functioning in the face of adversity and is influenced by both environmental and genetic factors. The identification of specific genetic factors and their biological pathways underpinning resilient functioning can help in the identification of common key factors, but heterogeneities in the operationalisation of resilience have hampered advances. We conducted a systematic review of genetic variants associated with resilience to enable the identification of general resilience mechanisms. We adopted broad inclusion criteria for the definition of resilience to capture both human and animal model studies, which use a wide range of resilience definitions and measure very different outcomes. Analyzing 158 studies, we found 71 candidate genes associated with resilience. OPRM1 (Opioid receptor mu 1), NPY (neuropeptide Y), CACNA1C (calcium voltage-gated channel subunit alpha1 C), DCC (deleted in colorectal carcinoma), and FKBP5 (FKBP prolyl isomerase 5) had both animal and human variants associated with resilience, supporting the idea of shared biological pathways. Further, for OPRM1, OXTR (oxytocin receptor), CRHR1 (corticotropin-releasing hormone receptor 1), COMT (catechol-O-methyltransferase), BDNF (brain-derived neurotrophic factor), APOE (apolipoprotein E), and SLC6A4 (solute carrier family 6 member 4), the same allele was associated with resilience across divergent resilience definitions, which suggests these genes may therefore provide a starting point for further research examining commonality in resilience pathways.
... Of interest in this regard is a recent study in subjects with a varying degree of susceptibility to depression that investigated the influence of COMT Val158Met on endocrine and subjective responses to a psychological stress task, showing an increased subjective response to psychological stress with increased Met loading in both healthy and depressed subjects, but a stronger endocrine response in controls with increased Met loading only (Jabbi et al., 2007a). These results do not only suggest that Met alleles are involved in subjective appraisals on situations that evoke negative affective states (ie stress-sensitivity), but the dissociation between subjective and endocrine responses to psychological stress in depressed subjects also suggests that it is in interaction with altered HPA axis functioning that this could lead to depression, although the issue of reverse causality needs to be addressed in future studies. ...
... Thus, quantitative trait differences may only become relevant in the presence of specific environments and in interaction with (deficits in) other biological mechanisms. For stress-sensitivity, this was supported by the recent study of Jabbi and colleagues (Jabbi et al., 2007a) who found stronger subjective reactions to a psychological stress task with increased COMT Val158Met ...
... It is not yet clear if and how a NE hyperactivity is individually determined. Genetic and epigenetic factors are surely important [67][68][69][70] . ...
... However, functions of the SNS are not only executive to input from the central nervous system, but could be affected by (local) hyper-or hypoactivity/hyper-or hyporeactivity of the gut, the heart, or any other organ. In addition, gene polymorphisms may modulate the efficacy of the catecholamines at receptor sites [69,85] . This may not only cause interindividual differences in the degree of sympathetically modulated stress responses, but also affect interoception of visceral stimuli, and thus the perceived emotional valence [86][87][88] . ...
Article
To facilitate the translation of basic research findings to clinical application, we conceptualized the principles of the crosstalk between brain and body, which constitute the stress response. While 'glandotropy' mainly refers to the pituitary-adrenal-axis, the traditional terms 'ergotropy' and 'trophotropy' refer to the autonomic nervous system. They were extended to the biogenic amine systems, which are functionally associated with the HPAA and ANS.
... In parallel, experimental studies have shown that COMT Val158Met variation has an impact on the cognitive and neurophysiological responses to acute stress in the laboratory. Increased plasma epinephrine and cortisol responses to laboratory-induced stress were observed in Met allele healthy controls compared to other genotype groups, however mixed patterns of association were observed in depressed patients and high-risk groups (Jabbi et al., 2007a). Accuracy on a working memory task was reduced after the presentation of a traumatic film (acute stressor) in Met homozygous participants, but was relatively improved in Val carriers (Qin et al., 2012). ...
... The functioning of the COMT Val158Met polymorphism may be moderated by other dopaminergic polymorphisms or variations within other genes ). An interaction including the 5-HTTLPR occurred (Jabbi et al., 2007a) only in the case of homozygous participants for COMT Val allele, where the 5-HTTLPR L allele had a protective effect in the case of stress (Conway et al., 2010). Moreover, carrying the COMT Met allele and DRD2 (rs6277) T allele was predictive of severe depression in a group of depressed patients, and was associated with decreased remission rates after treatment with ECT, however, this combination did not predict depression risk when compared to a control group (Huuhka et al., 2008). ...
Article
Depression is a common and disabling psychiatric disorder with a complex etiology, which includes predisposing risk genes and environmental stressors. Variation in the Catechol-O-Methyltransferase (COMT) gene, the Val158Met polymorphism in particular, has been extensively investigated in relation to clinical phenotypes of depression and, in parallel, neurocognitive processes. In this review, we bridge evidence from neuroimaging, behavioral and clinical studies that have examined the role of COMT variants on depression-relevant phenotypes. We observed that clinical phenotypes such as depression severity and diagnosis, or behavioral endophenotypes, are less reliably associated with COMT genetic variation. On the other hand, genetic effects are more discernible on brain systems of emotional processing. Specifically, the Met allele is associated with increased activity in limbic areas and prefrontal cortex, but is also more likely to have a better response to antidepressant treatment, compared to the Val allele. Gender and stress are important modulators of COMT genetic effects. On the basis of current evidence, we propose a tentative pathway through which the COMT gene may influence cognitive vulnerability to depression.
... Рассмотренные по отдельности ранговые индексы боли по сенсорным и аффективным характеристикам также показали статистически значимое различие средних и медиан между пациентами с Рис. 2. Оценка интенсивности боли по числовой рейтинговой шкале (ЧРШ) для гаплотипов с частотой не менее 3% (данные представлены в виде среднего и его 95%ДИ в порядке возрастания средних значений) Picture 2. Intensity pain estimation using numeric rating scale (NRS) for haplotypes with frequency not less than 3% (the results are presented as mean value and its 95%CI in ascending order of means) 15,38 (11,(11)(12)(13)(14)(15)(16)67) 26,67 (22,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)33) Примечание: данные представлены в виде медианы и интерквартильного размаха. РИБ сен -ранговый индекс боли сенсорный компонент; РИБ сен% -% составляющей рангового индекса боли сенсорного компонента; РИБ аф -ранговый индекс боли аффективный компонент; РИБ аф% -% составляющей рангового индекса боли аффективного компонента. ...
... Генетические различия в дофаминергической системе ЦНС (модифицированные, например, полиморфизмами гена СОМТ) могут приводить к различным сбоям в реакции гипоталамо-гипофизарной надпочечниковой системы. Носители Met / Met генотипа более подвержены этим нарушениям и имеют более высокий уровень кортизола, что снижает иммунную защиту и может способствовать росту опухоли [24,25]. Этот факт обусловливает важность использования медикаментозных и немедикаментозных методов, направленных на купирование тревоги и депрессии в программе лечения хронического болевого синдрома в онкологии у пациентов с наличием мутаций в гене СОМТ. ...
Article
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The objective is to study the effect of single-nucleotide polymorphisms (SNPs) of COMT gene on the formation and characteristics of chronic pain, level of anxiety and depression, effectiveness of analgesia in oncological patients. Material and Methods. The study includes 196 patients with oncological pathology. The formation of chronic pain syndrome was estimated in all patients one year after surgery using the assessment of pain intensity by numeric rating scale, pain questionnaire of McGill, PainDetect. Basing on the patients genotyping data the genotypes and haplotypes frequency distribution on SNPs of rs4680, rs740603, rs2097603=rs2070577, rs4633 of COMT gene was estimated. The relationship between different genotypes, haplotypes and chronic pain intensity, severity of ranking index of pain for sensor and affective characteristics on McGill scale, presence of neuropathic component of pain and anxiety was studied in all patients sample. The same analysis was carried out in order to clarify difference in morphine consumption (mg/24h) and severity of adverse side effects such as drowsiness, confusion and hallucinations. Results. It is found that after one year the pain syndrome was developed in 134 patients. It was showed that there is direct relationship between chronic pain intensity, anxiety level and presence of mutant allele on polymorphisms of rs4680 in exon and rs740603 in intron of COMT gene. There was also revealed inverse relationship between morphine requirement and presence of pointed polymorphisms in comparison with the patients who have GG genotype of these markers. Conclusion. The determination of pointed SNPs may be useful for choosing the optimal tactics of analgesia in patients with chronic oncological pain syndrome.
... In the context of a prolonged traumatic situation such as the COVID-19 pandemic, the two transmitters of greatest potential significance are noradrenaline, which mediates the "flight or fight" response to stress, and serotonin, which is involved in risk appraisal and in the emotions of sadness and anxiety . Variations in genes involved in regulating the function of these two transmitters, such as the catechol-O-methyltransferase (COMT) gene, the monoamine oxidase type A (MAOA) gene, the tryptophan hydroxylase type II gene (TPH2), and the serotonin transporter (SLC6A4), have been associated with significant variations in stress response and resilience in both human and animal subjects (Jabbi et al., 2007;Clukay et al., 2019;Gonzalez-Giraldo and Forero, 2020;Strekalova et al., 2020). Research in mice suggests that the noradrenergic system plays a particular role in influencing resilience to chronic stress (Isingrini et al., 2016), and that the activation of a specific serotonin receptor subtype (5HT 4 ) reduces both fear-like and depressive-like responses to chronic stress (Chen et al., 2020b). ...
... Early research into the genetics of resilience focused on candidate genes that were thought to influence the responsiveness of the stress axis, such as monoamine transmitters or HPA axis-related receptors (Jabbi et al., 2007;Derijk and de Kloet, 2008) and then grew to encompass the role of multiple gene-environment interactions, and other genetic variants (Daskalakis et al., 2013). Subsequent studies focused on more downstream molecular mediators of resilience. ...
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Healthcare workers are at a high risk of psychological morbidity in the face of the COVID-19 pandemic. However, there is significant variability in the impact of this crisis on individual healthcare workers, which can be best explained through an appreciation of the construct of resilience. Broadly speaking, resilience refers to the ability to successfully adapt to stressful or traumatic events, and thus plays a key role in determining mental health outcomes following exposure to such events. A proper understanding of resilience is vital in enabling a shift from a reactive to a proactive approach for protecting and promoting the mental well-being of healthcare workers. Research in the past decade has identified six areas that provide promising leads in understanding the biological basis of individual variations in resilience. These are: (1) the key role played by the monoamines noradrenaline and serotonin, (2) the centrality of the hypothalamic-pituitary-adrenal axis in influencing stress vulnerability and resilience, (3) the intimate links between the immune system and stress sensitivity, (4) the role of epigenetic modulation of gene expression in influencing the stress response, (5) the role played by certain neuropeptides as a natural “brake” mechanism in the face of stress, and (6) the neurobiological mechanisms by which environmental factors, such as exercise, diet, and social support, influence resilience to subsequent life events. Though much of this research is still in its early stages, it has already provided valuable information on which strategies – including dietary changes, lifestyle modification, environmental modification, psychosocial interventions, and even pharmacological treatments – may prove to be useful in fostering resilience in individuals and groups. This paper examines the above evidence more closely, with a specific focus on the challenges faced by healthcare workers during the COVID-19 pandemic, and provides suggestions regarding how it may be translated into real-world interventions, as well as how the more tentative hypotheses advanced in this field may be tested during this critical period.
... The catechol-O-methyltransferase (COMT) gene is in charge of encoding the COMT enzyme, an enzyme that degrades dopamine, norepinephrine and epinephrine and inhibits CRH release, which may lower HPA-axis activity (Jabbi et al., 2007). Research consistently demonstrates that Met-allele carriers that with low COMT enzyme show a greater HPA-axis stress response than Val/Val homozygotes, such as higher plasma adreno-cortico-tropic-hormone (ACTH) and cortisol response to stressors (Armbruster et al., 2012;Jabbi et al., 2007). ...
... The catechol-O-methyltransferase (COMT) gene is in charge of encoding the COMT enzyme, an enzyme that degrades dopamine, norepinephrine and epinephrine and inhibits CRH release, which may lower HPA-axis activity (Jabbi et al., 2007). Research consistently demonstrates that Met-allele carriers that with low COMT enzyme show a greater HPA-axis stress response than Val/Val homozygotes, such as higher plasma adreno-cortico-tropic-hormone (ACTH) and cortisol response to stressors (Armbruster et al., 2012;Jabbi et al., 2007). ...
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Research suggests that genetic variants that regulate the hypothalamic-pituitary-adrenal (HPA) axis function moderate the association between parenting and anxiety symptoms, but these studies have primarily focused on (i) individual genes with very small and unreliable effect and (ii) the role of mothers as opposed to fathers. Using a multilocus genetic profile score approach, the current study is the first to examine the moderation effect of HPA-axis multilocus genetic variants on the associations of both maternal and paternal parenting with adolescent anxiety symptoms. In a sample of Chinese Han adolescents (N = 772; 50.1% girls; Mage = 16.48 ± 1.40 years, range: 15–20 years), a theory-driven multilocus genetic profile score was computed by counting the numbers of alleles that were previously linked to heightened stress reactivity in six HPA-axis related genes. This HPA-axis related multilocus genetic profile score equivalently interacted with both maternal and paternal parenting in the prediction of adolescent anxiety symptoms. Consistent with cumulative polygenic plasticity hypothesis of differential susceptibility model, adolescents with more versus low alleles linked to heightened stress reactivity not only suffered more from poor maternal or paternal parenting quality, but also benefited more from high maternal or paternal parenting quality. However, none of the individual HPA-axis genes within this multilocus genetic profile score yielded a significant gene-by-environment (G × E) interaction when examined in isolation. The findings survived after internal replication analysis and a novel, valid influence statistic DFBETAS analysis, demonstrating the robustness of the results. The current study highlights the potential value of using a multilocus approach to understand G × E effects underlying anxiety symptoms and emphasizes the role of both mothers and fathers in such gene-parenting interactions, especially in Chinese families.
... S tudies on epigenetics are changing how we interpret animal behavior and development (Bredy et al. 2010;Crews 2010;Curley and Mashoodh 2010;Meaney 2010;Miller 2010;Svrakic and Cloninger 2010;Weaver et al. 2004;Zhang and Meaney 2010). In the past, most behavioral differences were ascribed to polymorphism in either select groups of genes or physiochemical differences of unknown etiology (Bray 2008;Hamer 2002;Inoue and Lupski 2003;Jabbi et al. 2007;Kreek and LaForge 2007;Lee 2007;Mancama et al. 2003;Mantione et al. 2010;Proudnikov et al. 2008;Zhou et al. 2008;Zill et al. 2002). However, it is becoming apparent that at least some of these differences in behavior are related to epigenetic changes stemming from early social or developmental experience (Bredy et al. 2010;Crews 2010;Curley and Mashoodh 2010;Meaney 2010;Miller 2010;Svrakic and Cloninger 2010;Weaver et al. 2004;Zhang and Meaney 2010). ...
Article
Emerging evidence suggests that epigenetic-based mechanisms contribute to various aspects of sex differences in brain and behavior. The major obstacle in establishing and fully understanding this linkage is identifying the traits that are most susceptible to epigenetic modification. We have proposed that sexual selection provides a conceptual framework for identifying such traits. These are traits involved in intrasexual competition for mates and intersexual choice of mating partners and generally entail a combination of male-male competition and female choice. These behaviors are programmed during early embryonic and postnatal development, particularly during the transition from the juvenile to adult periods, by exposure of the brain to steroid hormones, including estradiol and testosterone. We evaluate the evidence that endocrine-disrupting compounds, including bisphenol A, can interfere with the vital epigenetic and gene expression pathways and with the elaboration of sexually selected traits with epigenetic mechanisms presumably governing the expression of these traits. Finally, we review the evidence to suggest that these steroid hormones can induce a variety of epigenetic changes in the brain, including the extent of DNA methylation, histone protein alterations, and even alterations of noncoding RNA, and that many of the changes differ between males and females. Although much previous attention has focused on primary sex differences in reproductive behaviors, such as male mounting and female lordosis, we outline why secondary sex differences related to competition and mate choice might also trace their origins back to steroid-induced epigenetic programming in disparate regions of the brain.
... Genetic differences in COMT may underlie individual differences in response to psychological and physical stressful challenges (Smolka et al., 2005;Zubieta et al., 2003). An association between COMT genotype and history of violent behavior has been seen in some human studies (Jabbi et al., 2007;Lachman, Nolan, Mohr, Saito, & Volavka, 1998), and COMT is a possible candidate gene involved in the pathogenesis of major depressive disorders and schizophrenia. ...
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The sympathetic nervous system not only regulates cardiovascular and metabolic responses to stress but also is altered by stress. The sympathoneural and sympathoadrenomedullary systems are modified by different metabolic pathways and have different responses to short- and to long-term stressors. Stress also induces nonneuronal catecholamine enzymes, primarily through corticosteroids. Catecholamine synthetic enzymes are induced by different pathways in response to short- and long-term acting stressors, like cold exposure or immobilization, and differently in the sympathetic ganglia and the adrenal medulla. However, a long-term exposure to one stressor can increase the response to a second, different stressor. Tyrosine hydroxylase gene transcription increases after only 5min of immobilization through phosphorylation of CREB, but this response is short lived. However, repeated stress gives a longer-lived response utilizing transcription factors such as Egr-1 and Fra-2. Glucocorticoids and ACTH also induce sympathoneural enzymes leading to distinct patterns of short-term and long-lived activation of the sympathetic nervous system. Nonneuronal phenylethanolamine N-methyltransferase (PNMT) develops early in the heart and then diminishes. However, intrinsic cardiac adrenergic cells remain and nonneuronal PNMT is present in many cells of the adult organism and increases in response to glucocorticoids. Both stress-induced and administered glucocorticoids induce fetal PNMT and hypertension. Human stressors such as caring for an ill spouse or sleep apnea cause a persistent increase in blood norepinephrine, increased blood pressure, and downregulated catecholamine receptors. Hypertension is associated with a loss of slow-wave sleep, when sympathetic nerve activity is lowest. These findings indicate that stress-induced alteration of the sympathetic nervous system occurs in man as in experimental animals.
... It is of note that COMT genotype has been associated with the endocrine response to psychological stress (Alexander et al., 2011;Jabbi et al., 2007;Walder et al., 2010). Homozygosity for the minor allele (G) of rs4680, which reduced COMT activity, has been correlated with increased cortisol secretion in several studies. ...
Article
Polycystic ovary syndrome (PCOS) is an endocrine disorder that affects 5-8% of reproductive age women. The primary features of PCOS are hyperandrogenemia, chronic anovulation and infertility. It has been suggested that defects in ovarian steroid metabolism contribute to the follicular growth arrest and abnormal production of ovarian steroid hormones that are characteristic of PCOS. 2-Methoxyestradiol (2-ME) is formed by the action of catechol-O-methyltransferase (COMT) on 2-hydroxyestradiol. COMT expression is increased in the follicles and ovarian stroma of women with PCOS. Moreover, 2-ME decreases granulosa cell proliferation and steroidogenesis, raising the possibility that ovarian dysfunction associated with PCOS is due, in part, to increased synthesis of 2-ME resulting from increased COMT activity. Four single-nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4818, rs4680) in the COMT gene characterize haplotypes, which are associated with large variations in COMT enzymatic activity. The aim of this study was to determine whether individual COMT SNPs and the COMT haplotypes are associated with PCOS using a family-based test of association and linkage. Additionally, we examined the relationships between COMT SNPs and haplotypes with quantitative variables usually assessed in the evaluation of women with PCOS. There were no significant correlations between genotype and total testosterone, non-SHBG bound testosterone and BMI. However, we found that the prolactin level in women with PCOS varied significantly with COMT haplotype, and suggest that this association reflects a genetic factor influencing the stress response. Our findings suggest that common variants and haplotypes of the COMT gene are not major contributors to risk for PCOS, but that COMT genotype may influence prolactin levels.
... In particular, the methionine allele has been linked to negative emotionality and anxiety (Enoch, Xu, Ferro, Harris, & Goldman, 2003;Olsson et al., 2005;Stein, Fallin, Schork, & Gelernter, 2005), elevated startle response (Armbruster et al., 2011;Montag et al., 2008), and increased limbic and prefrontal activation in response to negative stimuli (Drabant et al., 2006;Rasch et al., 2010;Williams et al., 2010). The COMT methionine allele has also been shown to be associated with a greater stress response to laboratory stressors, such as the Trier Social Stress Test in adults (Alexander et al., 2011;Jabbi et al., 2007) and in children (Armbruster et al., 2011). ...
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Gene-environment correlations (rGE) have been demonstrated in behavioral genetic studies, but rGE have proven elusive in molecular genetic research. Significant gene-environment correlations may be difficult to detect because potential moderators could reduce correlations between measured genetic variants and the environment. Molecular genetic studies investigating moderated rGE are lacking. This study examined associations between child catechol-O-methyltransferase genotype and aspects of positive parenting (responsiveness and warmth), and whether these associations were moderated by parental personality traits (neuroticism and extraversion) among a general community sample of third, sixth, and ninth graders (N = 263) and their parents. Results showed that parent personality traits moderated the rGE association between youths' genotype and coded observations of positive parenting. Parents with low levels of neuroticism and high levels of extraversion exhibited greater sensitive responsiveness and warmth, respectively, to youth with the valine/valine genotype. Moreover, youth with this genotype exhibited lower levels of observed anger. There was no association between the catechol-O-methyltransferase genotype and parenting behaviors for parents high on neuroticism and low on extraversion. Findings highlight the importance of considering moderating variables that may influence child genetic effects on the rearing environment. Implications for developmental models of maladaptive and adaptive child outcomes, and interventions for psychopathology, are discussed within a developmental psychopathology framework.
... Clear evidence indicates a mutual predisposition ; for example, biologically based MDD is predicted nearly equally by the presence of familial MDD or FM. This mutual predisposition is likely due to a combination of genetic and environmental factors [12, 19,7879808182. These predisposed individuals are particularly vulnerable to a precipitating event that triggers FM or MDD. ...
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Fibromyalgia and depression might represent two manifestations of affective spectrum disorder. They share similar pathophysiology and are largely targeted by the same drugs with dual action on serotoninergic and noradrenergic systems. Here, we review evidence for genetic and environmental factors that predispose, precipitate, and perpetuate fibromyalgia and depression and include laboratory findings on the role of depression in fibromyalgia. Further, we comment on several aspects of fibromyalgia which support the development of reactive depression, substantially more so than in other chronic pain syndromes. However, while sharing many features with depression, fibromyalgia is associated with somatic comorbidities and absolutely defined by fluctuating spontaneous widespread pain. Fibromyalgia may, therefore, be more appropriately grouped together with other functional pain disorders, while psychologically distressed subgroups grouped additionally or solely with affective spectrum disorders.
... Glucocorticoids, the stress hormone, was found to inhibit COMT [117,152] and the levels of serum adrenaline were found to progressively increase with the greater number of COMT108/158 alleles under the same conditions of stimulation [153]. In the control subjects in this study the serum adrenaline levels rose from 0.15, to 0.29, to 0.5 for the COMT Val/Val, Val/Met and Met/Met alleles, respectively. ...
Article
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Genetic polymorphisms in the Catechol O-Methyltransferase (COMT) gene have been linked to increased pain sensitivity in a number of studies. A literature search was performed to integrate the current knowledge of the gene, its regulation, influences of the polymorphisms upon enzyme function and its population distributions. Assessment also includes the current knowledge of the enzyme structure, isoforms, function and metabolic activities, substrates, and products. Other gene polymorphisms which may influence the components involved within the COMT enzymatic reaction, such as folate metabolism polymorphisms and cofactor availability, were also briefly assessed. A review of enzyme agonists and antagonist and how these may influence the enzymes functions, its substrates and products is undertaken in an attempt to understand the potential interactions between COMT and factors that may influence enzyme activity in the presence or absence of the COMT polymorphic forms.
... The biological mechanisms of elevated cortisol levels in schizophrenia and bipolar disorder may be associated with the predisposition to psychosis, environmental effects or an interaction of the two (Wang et al. 2011;Aina 2013;Perroud et al. 2011). Predisposing genetic factors may include common variants on single nucleotide polymorphisms (SNPs) in genes associated with cortisol metabolism (SRD5A2) (Steen et al. 2010), the regulation of cortisol (glucocorticoid receptor, NR3C1) (Schatzberg et al. 2014), dopamine catabolism (catechol-omethyltransfease COMT; dopamine D4 receptor gene (DRD4) (Jabbi et al. 2007), inhibitory neurotransmittors (GABA a6 receptor subunit gene; GABRA6) (Uhart et al. 2004) and stress-vulnerability (serotonin transporter-linked polymorphic region; 5-HTTLPR) (Miller et al. 2013). Similarly, environmental factors such as substance abuse (Lopez- Larson et al. 2011;Gavrieli et al. 2011), sleep deprivation (Spiegel et al. 1999), dietary changes (Cheng and Li 2012), lower socioeconomic status (Rudolph et al. 2014) and a lower level of education (Karlamangla et al. 2013) may contribute to the increased cortisol. ...
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The role of stress in precipitating psychotic episodes in schizophrenia and bipolar disorder has long been acknowledged. However, the neurobiological mechanism/s of this association have remained elusive. Current neurodevelopmental models of psychosis psychosis implicate early dysfunction in biological systems regulating hypothalamic-pituitary-adrenal axis and immune function, with long-term effects on the development of the brain networks responsible for higher order cognitive processes and stress reactivity in later life. There is also increasing evidence of childhood trauma in psychosis, and its impact on the development of brain systems regulating stress. These findings are emerging in the context of a new era of epigenetic epigenetic methods facilitating the study of environmental effects on gene expression. The evidence is thus converging: exposure to stress at critical periods in life may be an important factor in the development of the brain dysfunction that represents psychosis vulnerability, rather than merely interacting with an independent 'biological vulnerability' to manifest in psychosis.
... Previous research on mental disorders such as depression, substance use disorder and ADHD has suggested a maladaptive reward pathway due to dysfunctional dopaminergic neurotransmission (Beck et al., 2009;Forbes et al., 2006;Pizzagalli et al., 2009;Plichta et al., 2009;Scheres et al., 2007;Wrase et al., 2007). However, although carriers of the COMT Met allele seemed prone to inefficient emotion regulation (Drabant et al., 2006) and higher vulnerability to stress (Jabbi et al., 2007), no direct association between COMT and depression has been substantiated so far (Antypa et al., 2013). Similarly, the majority of studies examining the association of COMT with alcoholism or illicit drug abuse failed to reveal a significant relationship (Tammimaki and Mannisto, 2010;Tunbridge et al., 2012). ...
... Numerous studies have examined the relation between MDD and COMT Val158Met (Kunugi et al. 1997;Ohara et al. 1998;Frisch et al. 1999;Massat et al. 2005;Arias et al. 2006;Garriock et al. 2006;Serretti et al. 2006;Jabbi et al. 2007;Huuhka et al. 2008;Zalsman et al. 2008;Potter et al. 2009;Massat et al. 2011;Opmeer et al. 2013;Chiesa et al. 2014;Hayashi et al. 2014;Shen et al. 2014;Wang et al. 2014;Pandolfo et al. 2015), but the results remain inconclusive. Massat and colleagues found a higher Val allele frequency in early-onset MDD (Massat et al. 2005;Massat et al. 2011). ...
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The COMT (catechol-O-methyltransferase) Val158Met polymorphism (rs4680) is a potential susceptibility variant for major depressive disorder (MDD). Although many genetic studies have examined the association between MDD and this polymorphism, the results were inconclusive. In the present study, we conducted a series of meta-analyses of samples consisting of 2905 MDD cases and 2403 controls with the goal of determining whether this variant indeed has any effect on MDD. We revealed a significant association in the comparison of Val/Val + Val/Met vs. Met/Met (OR =1.180; 95 % CI = 1.019, 1.367; P = 0.027), Val/Met vs. Val/Val (OR =1.18; 95 % CI = 1.038, 1.361; P = 0.013), and Val/Met vs. Met/Met (OR =1.229; 95 % CI = 1.053, 1.435; P = 0.009). Further meta-analyses of samples with European ancestry demonstrated a significant association of this SNP with MDD susceptibility in Val/Val + Val/Met vs. Met/Met (OR =1.231, 95 % CI = 1.046, 1.449; P = 0.013) and Val/Met vs. Met/Met (OR =1.284, 95 % CI = 1.050, 1.484; P = 0.012). For the samples with East Asian ancestry, we found a significant association in both allelic (Val vs. Met: OR =0.835; 95 % CI = 0.714, 0.975; P = 0.023) and genotypic (Met/Met + Val/Met vs. Val/Val: OR =1.431, 95 % CI = 1.143, 1.791; P = 0.002; Val/Met vs. Val/Val: OR =1.482, 95 % CI = 1.171, 1.871; P = 0.001) analyses. No evidence of heterogeneity among studies or publication bias was observed. Together, our results indicate that the COMT Val158Met polymorphism is a vulnerability factor for MDD with distinct effects in different ethnic populations.
... In addition to its role in modulating brain regions important for cognition (Savitz et al. 2006) and reward (Nestler et al. 2002), dopamine also regulates the stress system which is reciprocally connected with the mesocorticolimbic dopaminergic systems (Chrousos 2009). Variations in the COMT Val158Met polymorphism moderate corticolimbic responses to emotional stimuli (Drabant et al. 2006;Smolka et al. 2005), responses to physical and emotional stressors (Jabbi et al. 2007;Zubieta et al. 2003), and depressive symptoms in children with early social deprivation (Drury et al. 2010). To our knowledge however, this potential interaction between COMT Val158Met polymorphism and SLEs on MDD course has not been reported. ...
Article
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Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.
... Vulnerable endo-phenotypes have indeed been reported, suggesting that the subjective perception of stress, and by inference of life events, may render individuals more prone to develop depression (e.g. Jabbi et al. 2007a, b). But again: differences between groups, not between individuals were significant. ...
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Considering psychiatry as a medical discipline, a diagnosis identifying a disorder should lead to an effective therapy. Such presumed causality is the basis of evidence-based psychiatry. We examined the strengths and weaknesses of research onto the causality of relationship between diagnosis and therapy of major depressive disorder and suggest what could be done to strengthen eventual claims on causality. Four obstacles for a rational evidence-based psychiatry were recognised. First, current classification systems are scientifically nonfalsifiable. Second, cerebral processes are-at least to some extent-nondeterministic, i.e. they are random, stochastic and/or chaotic. Third, the vague or lack of relationship between therapeutic regimens and suspected pathogenesis. Fourth, the inadequacy of tools to diagnose and delineate a functional disorder. We suggest a strategy to identify diagnostic prototypes that are characterised by a limited number of parameters (symptoms, markers and other characteristics). A prototypical diagnosis that may either support or reject particular elements of current diagnostic systems. Nevertheless, one faces the possibility that psychiatry will remain a relatively weak evidence-based medical discipline.
... Several studies have found that people with homozygous Met alleles have more frequent and intense experiences of negative affect such as anxiety, stress, anger, and depression (Enoch, Xu, Ferro, Harris, & Goldman, 2003;Jabbi et al., 2007;Perroud et al., 2010;Smolka et al., 2005;Zubieta et al., 2003). Jabbi and colleagues (2007), for example, measured female adolescents' subjective stress and endocrine response to stressful tasks performed in the laboratory (e.g., timed mental arithmetic, giving a speech). ...
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The catechol-O-methyltransferase (COMT_Val158Met) genetic polymorphism has been linked to variation in affective well-being. Compared with Val carriers, Met carriers experience lower affective well-being. In parallel, research on aging and affective experience finds that younger adults experience poorer affective well-being than older adults. This study examined how COMT and age may interact to shape daily affective experience across the life span. Results suggest that Met (vs. Val) carriers experience lower levels of affective well-being in younger but not in older ages. These findings suggest that age-related improvements in emotional functioning may offset genetic vulnerabilities to negative affective experience. (PsycINFO Database Record
... Despite the prevalence of depression and its considerable impact in public health, its pathophysiological mechanisms remain poorly understood (Krishnan and Nestler, 2008). Epidemiological, clinical, and basic research studies have revealed the existence of a complex interplay between genetic and environmental elements, with the physiological and psychological history of the subject playing a particularly important role (McEwen and Stellar, 1993;Cryan and Slattery, 2007;Jabbi et al., 2007;Jacobson and Cryan, 2007). Knowledge of the risk factors contributing to susceptibility to stress and of the mechanisms by which they act in the subsequent development of depression is crucial (Brown et al., 1987;Post, 1992;Kessler, 1997;de Kloet et al., 2005). ...
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A stressful event increases the risk of developing depression later in life, but the possible predisposing factors remain unknown. Our study aims to characterize latent vulnerability traits underlying the development of depressive disorders in adult animals. Four weeks after a priming stressful event, serum corticosterone concentration returned to control values in all animals, whereas the other biological parameters returned to basal level in only 58% of animals (called nonvulnerable). In contrast, 42% of animals displayed persistent decreased serum and hippocampus BDNF concentrations, reduced hippocampal volume and neurogenesis, CA3 dendritic retraction and decrease in spine density, as well as amygdala neuron hypertrophy, constituting latent vulnerability traits to depression. In this group, called vulnerable, a subsequent mild stress evoked a rise of serum corticosterone levels and a "depressive" phenotype, in contrast to nonvulnerable animals. Intracerebroventricular administration of 7,8-dihydroxyflavone, a selective TrkB receptor agonist, dampened the development of the "depressive" phenotype. Our results thus characterize the presence of latent vulnerability traits that underlie the emergence of depression and identify the association of low BDNF with normal corticosterone serum concentrations as a predictive biomarker of vulnerability to depression.
... Given that the Met allele is associated with enhanced DA signaling in the PFC, our findings are theoretically sound and consistent with the inverted U-shaped curve theory of DA activity (Goldman-Rakic et al., 2000 (Goldman-Rakic et al., 2000), it is conceivable that increased stress or emotion task engagement would result in higher cortisol levels in the Met allele carriers relative to the Val homozygotes. In fact, the Met allele has already been shown to associate with higher cortisol levels compared to the Val allele in response to stress (Jabbi et al., 2007;Oswald, McCaul, Choi, Yang, & Wand, 2004). Our finding that Val homozygotes had higher cortisol levels than Met allele carriers, under nonstress conditions, is also consistent with the idea that high afternoon cortisol levels are associated with mood impairments (Christensen et al., 1983(Christensen et al., , 1985. ...
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Introduction We tested the extent to which the catechol‐O‐methyltransferase (COMT) Val158Met polymorphism is associated with affective state and evening cortisol levels. We limited our study to women as previous research suggests that the link between COMT genotype and psychological health is entangled by sex differences. Materials and Methods The participants were assessed on measures of anxiety, mood disturbance, depressive symptomatology, and perceived stress. We also evaluated participants on a quality of life measures that included two emotion domains and two physical domains (physical health and environment). Results We found that under normal (nonstress) conditions, the COMT A allele (Met carriers, higher dopamine) associates with healthier affect and lower afternoon cortisol levels in women. These effects were limited to affective measures and not to physical or environmental quality of life. Conclusions These findings help to shed light on the complex nature of COMT and emotion, and suggest that both sex and task condition (stress vs. nonstress) should be considered when examining the relationship between COMT genotype and emotion.
... Functional interactions between FKBP5 and monoaminergic genes at the SNP levels were also shown to predict adaptive peripheral corticotropin-releasing hormone (CRH) response [59]. These results are in line with evidence showing that SNP variations 1) in monoaminergic genes impact endocrine and behavioral stress responses [60][61], and 2) in the corticotropin-releasing hormone receptor (CRHR) gene interactions with early life environmental adversity [62] to impact later-onset mood disorders [63]. ...
Article
Introduction: Mood and anxiety disorders are a leading contributor to the global burden of diseases. Comorbid mood and anxiety disorders have a lifetime prevalence of over 20% globally and increases the risk for suicide, one of the leading causes of death in Europe and North America. Areas covered: In this narrative review, the authors highlight recent advances in the understanding of multi-level neurobiological mechanisms for normal and pathological human affective functioning. The authors then address the complex interplay between environmental adversity and molecular-genetic mediators of these neurobiological correlates of affective symptoms. The molecular focus is strategically limited to three genes GTF2i, BDNF, and FKBP5 that are respectively involved in transcriptional, neurodevelopmental and neuroendocrine pathway mediation of affective functions. The importance of these genes is illustrated with studies of a) copy number variants, b) genome-wide association studies (GWAS), and c) candidate gene sequence variant associations with affective disorder etiology. The authors conclude this review by highlighting the predictive values of integrative neurobiological processes that influenced by gene-environment interactions and mediate affective disorder symptoms and their management. Expert opinion: Given the documented relevance of GTF2i, BDNF and FKBP5 genes in transcriptional, neurodevelopmental and neuroimmune processes respectively, the authors reviewed the putative roles of these genes in neurobiological mediation of adaptive affective responses to environmental challenges. The authors discussed the importance of studying the dosage effects of these genes in understanding mood and anxiety disorder risk biology, and how such targeted neurogenetic studies could guide precision identification of novel pharmacotherapeutic targets and aid in prediction of treatment response.
... That not all patients who receive opioids develop OIH (Suzan et al., 2013) may be related to differences in levels of stress as well as genetic and/or developmental differences in stress axis responsiveness. OIH was found to be strongest in patients with the met/met catechol-O-methyltransferase polymorphism, which is responsible for markedly greater stress-induced increases in plasma levels of stress axis mediators (Jabbi et al., 2007;Jensen et al., 2009). Patients with preoperative stress are more vulnerable to postoperative pain (Munafo and Stevenson, 2001) and, stress exacerbates OIH (Edwards et al., 2011(Edwards et al., , 2016Laboureyras et al., 2014). ...
Article
Opioid-induced hyperalgesia (OIH) is a serious adverse event produced by opioid analgesics. Lack of an in vitro model has hindered study of its underlying mechanisms. Recent evidence has implicated a role of nociceptors in OIH. To investigate the cellular and molecular mechanisms of OIH in nociceptors, in vitro, subcutaneous administration of an analgesic dose of fentanyl (30 μg/kg, s.c.) was performed in vivo in male rats. Two days later, when fentanyl was administered intradermally (1 μg, i.d.), in the vicinity of peripheral nociceptor terminals, it produced mechanical hyperalgesia (OIH). Additionally, two days after systemic fentanyl, rats had also developed hyperalgesic priming (opioid-primed rats), long-lasting nociceptor neuroplasticity manifested as prolongation of prostaglandin E2 (PGE2) hyperalgesia. OIH was reversed, in vivo, by intrathecal administration of cordycepin, a protein translation inhibitor that reverses priming. When fentanyl (0.5nM) was applied to dorsal root ganglion (DRG) neurons, cultured from opioid-primed rats, it induced a mu-opioid receptor (MOR)-dependent increase in [Ca2+]i in 26% of small-diameter neurons and significantly sensitized (decreased action potential rheobase) weakly IB4-positive and IB4-negative neurons. This sensitizing effect of fentanyl was reversed in weakly IB4-positive DRG neurons cultured from opioid-primed rats after in vivo treatment with cordycepin, to reverse of OIH. Thus, in vivo administration of fentanyl induces nociceptor neuroplasticity, which persists in culture, providing evidence for the role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH.SIGNIFICANCE STATEMENTClinically used mu-opioid receptor agonists such as fentanyl can produce hyperalgesia and hyperalgesic priming. We report on an in vitro model of nociceptor neuroplasticity mediating this opioid-induced hyperalgesia (OIH) and priming, induced by fentanyl. Using this model, we have found qualitative and quantitative differences between cultured nociceptors from opioid naïve and opioid primed animals, and provide evidence for the important role of nociceptor MOR-mediated calcium signaling and peripheral protein translation, in the weakly IB4-binding population of nociceptors, in OIH. These findings provide information useful for the design of therapeutic strategies to alleviate OIH, a serious adverse event of opioid analgesics.
... 24 Finally, polymorphisms on catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and glutamate solute carrier family 1 member 3 (SLC1A3) genes were also included in our analysis, given the large body of literature implicating polymorphisms in these genes with impairment in stress response. [25][26][27] Eighteen SNPs from the 14 selected genes (HTR1A, HTR2A, HTR1B, TPH1, TPH2, SLC6A4, CNR1, FAAH, FKBP5, CRHR1, NR3C1, COMT, BDNF and SLC1A3) were included in our analysis (table 1). Priority was given to functional SNPs or SNPs within regulatory regions using online genetic database ensemble (http://www. ...
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Background Functional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD. Methods Sixty-nine patients with a ‘clinically defined’ diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala–frontal connectivity was analysed using a whole-brain seed-based approach. Results Among the SNPs analysed, a tryptophan hydroxylase 2 ( TPH2 ) gene polymorphism—G703T—significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity. Conclusions This is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype.
... COMT maps to chromosome 22q11.21-q11.23, a region of particular interest because it is frequently included in the velocardiofacial syndrome (VCFS) deletion region (Grossman et al. 1992) Numerous genetic associations have been reported to several single nucleotide polymorphism (SNPs) or haplotypes at the COMT locus. These include VCFS-related traits (Bearden et al., 2005;Bearden et al.,2004;Gothelf et al., 2005;Gothelf et al.,2006;Lachman et al., 996), schizophrenia (Lachman et al., 1996;Shifman et al., 2002), anxiety-related personality traits (Stein et al., 2005), pain sensitivity (Diatchenko et al., 2005;Nackley et al., 2006), psychological stress response (Jabbi et al., 2007), and nicotine dependence (Beuten et al.,2006;Guo et al., 2007), among other traits. COMT haplotypes code for varying COMT enzymatic activity (Diatchenko et al., 2005), and associate with variation in mRNA structure and stability (Nackley et al., 2006). ...
Article
Catechol-O-methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine-induced paranoia (CIP) in African-American (AA) and European-American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family-controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (P = 0.05). In EAs, the best-known marker, rs4680 (Val158Met), was nominally significant in additive models (P = 0.03). SNP rs174696 also showed nominal significance in additive models (P = 0.02). We considered the three SNPs (rs737866-rs4680-rs174696) together in haplotype analysis in both family populations, using HBAT. The A-A-T haplotype was significantly associated with CIP in EAs (Z = 2.845; P = 0.0044, global P = 0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A-A-T haplotype was significantly associated to CIP in the AA unrelated population (P = 0.0015). Two haplotypes, A-G-C and A-A-C, were significant in the EA unrelated population (P = 0.001 and 0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family-controlled and unrelated-affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine.
... 4 psychosocial stress and sickness, that are also known to strongly predict the development of MDD independently of genetic effects. [6][7][8][9] We suggest that better understanding of physiological processes that transduce these environmental risks into pathology may lead to novel therapeutic strategies for the treatment of MDD. 10 Herein, we focus on inflammation, a physiological process that is activated in a similar manner by a diverse range of reliably depressogenic environmental factors (Table).* Conversely, interventions that reduce depressive symptoms have been reported to lower inflammatory and/or increase anti-inflammatory, immunoregulatory activity in the body and brain (Table). ...
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Inflammation is increasingly recognized as contributing to the pathogenesis of major depressive disorder (MDD), even in individuals who are otherwise medically healthy. Most studies in search of sources for this increased inflammation have focused on factors such as psychosocial stress and obesity that are known to activate inflammatory processes and increase the risk for depression. However, MDD may be so prevalent in the modern world not just because proinflammatory factors are widespread, but also because we have lost contact with previously available sources of anti-inflammatory, immunoregulatory signaling. To examine evidence that disruptions in coevolved relationships with a variety of tolerogenic microorganisms that were previously ubiquitous in soil, food, and the gut, but that are largely missing from industrialized societies, may contribute to increasing rates of MDD in the modern world. Relevant studies were identified using PubMed and Ovid MEDLINE. Included were laboratory animal and human studies relevant to immune functioning, the hygiene hypothesis, and major depressive disorder identified via PubMed and Ovid MEDLINE searches. Studies were reviewed by all authors, and data considered to be potentially relevant to the contribution of hygiene-related immune variables to major depressive disorder were extracted. Significant data suggest that a variety of microorganisms (frequently referred to as the "old friends") were tasked by coevolutionary processes with training the human immune system to tolerate a wide array of non-threatening but potentially proinflammatory stimuli. Lacking such immune training, vulnerable individuals in the modern world are at significantly increased risk of mounting inappropriate inflammatory attacks on harmless environmental antigens (leading to asthma), benign food contents and commensals in the gut (leading to inflammatory bowel disease), or self-antigens (leading to any of a host of autoimmune diseases). Loss of exposure to the old friends may promote MDD by increasing background levels of depressogenic cytokines and may predispose vulnerable individuals in industrialized societies to mount inappropriately aggressive inflammatory responses to psychosocial stressors, again leading to increased rates of depression. Measured exposure to the old friends or their antigens may offer promise for the prevention and treatment of MDD in modern industrialized societies.
... Individuals with higher resilience mostly make use of their personality characteristics to minimize the hazardous effect on their health outcomes of stress placed on them by disasters [30]. Research suggests that predictors of the resilience of an individual are often determined by a wide range of factors which stems from genetics, biological, psychological, and environmental factors [31][32][33]. Identifying the predictors of resilience for individuals and communities affected by natural disasters of a higher magnitude, such as the Fort McMurray wildfires, is an essential priority for psychiatric research in that the understanding of positive adaptation to stressors may help with prevention plans and also positively influence the required interventions aimed at helping the individuals at risk to recover from these inimical situations and their related psychological problems [34]. Previous studies have sought to examine the long-term effects of the Fort McMurray wildfires of 2016 by evaluating the predictors and prevalence of likely mental conditions such as major depressive disorder (MDD), generalized anxiety disorder (GAD), and PTSD [1,4]. ...
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Background: The Fort McMurray wildfire of 3 May 2016 was one of the most devastating natural disasters in Canadian history. Although resilience plays a crucial role in the daily functioning of individuals by acting as a protective shield that lessens the impact of disasters on their mental well-being, to date little is known about the long-term impact of wildfires on resilience and associated predictors of low resilience. Objectives: The objective of the study was to assess the prevalence and predictors of resilience among residents of Fort McMurray five years after the wildfires. Method: This was a quantitative cross-sectional study. A self-administered online survey which included standardized rating scales for resilience (BRS), anxiety (GAD-7), depression (PHQ-9), and post-traumatic stress disorder (PTSD)(PCL-C) was used to determine the prevalence of resilience as well as its demographic, clinical, and wildfire-related predictors. The data were collected between 24 April and 2 June 2021 and analyzed using the Statistical Package for Social Sciences (SPSS) version 25 using univariate analysis with a chi-squared test and binary logistic regression analysis. Results: A total of 186 residents completed the survey out of 249 who accessed the online survey, producing a response rate of 74.7%. Most of the respondents were females (85.5%, 159), above 40 years of age (81.6%, 80), employed (94.1%, 175), and in a relationship (71%, 132). Two variables-having had PTSD symptoms (OR = 2.85; 95% CI: 1.06-7.63), and age-were significant predictors of low resilience in our study. The prevalence of low resilience in our sample was 37.4%. Conclusions: Our results suggest that age and the presence of PTSD symptoms were the independent significant risk factors associated with low resilience five years after the Fort McMurray wildfire disaster. Further research is needed to enhance understanding of the pathways to resilience post-disaster to identify the robust predictors and provide appropriate interventions to the most vulnerable individuals and communities.
... Therefore , genetic variations leading to functional diVerences within the dopaminergic system may contribute to alterations of HPA-axis reactivity. In line with the assumption of the potential role of dopamine in lower eYcacy of coping strategies during exposure to stress, a signiWcant association was observed between elevated cortisol responses during a public speaking paradigm and presence of the Met158 allele of the COMT gene (Jabbi et al. 2007). Homozygosity for the Met158 allele has also been associated with reduced ability to extinguish conditioned fear (Lonsdorf et al. 2009). ...
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Dopamine plays a key role in reward behavior, yet the association of drug dependence as a chronic, relapsing disorder with the genes encoding the various dopaminergic receptor subtypes remains difficult to delineate. In the context of subsequent genome-wide association (GWAS) research and post-GWAS investigations, we summarize the novel data that link genes encoding molecules involved in the dopaminergic system (dopamine receptors, transporter and enzymes in charge of its metabolism) to drug addiction. Recent reports indicate that the heritability of drug addiction should be high enough to allow a significant role for a specific set of genes, and the available genetic studies, which might not be already conclusive because of the heterogeneity of designs, methods and recruited samples, should support the idea of a significant role of at least one gene related to dopaminergic system. Evolutionary changes in primates and non-primate animals of genes coding for molecules involved in dopaminergic system highlight why addictive disorders are mainly limited to humans. Restricting the analyses to more specific intermediate phenotypes (or endophenotypes) such as attention allocation, stress reactivity, novelty seeking, behavioral disinhibition and impulsivity, instead of the broad addictive disorder concept can be instrumental to identify novel genes associated with these traits in the context of genome-wide studies.
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The allostatic load (AL) model represents an interdisciplinary approach to comprehensively conceptualize and quantify chronic stress in relation to pathologies throughout the life cycle. This article first reviews the AL model, followed by interactions among early adversity, genetics, environmental toxins, as well as distinctions among sex, gender, and sex hormones as integral antecedents of AL. We next explore perspectives on severe mental illness, dementia, and caregiving as unique human models of AL that merit future investigations in the field of developmental psychopathology. A complimenting transdisciplinary perspective is applied throughout, whereby we argue that the AL model goes beyond traditional stress-disease theories toward the advancement of person-centered research and practice that promote not only physical health but also mental health.
Article
Catechol-O-methyltransferase, an enzyme involved in regulating brain catecholamine levels, has been implicated in anxiety, pain and/or stress responsivity. Elements of this putative association remain unclarified, notably whether: (a) COMT variation modulates responses to acute and/or chronic stress equally; (b) acute pharmacological inhibition of COMT produces comparable effects on anxiety to that observed after deletion of the COMT gene; (c) COMT genotype modulates action of anxiolytic drugs. We aimed to further investigate the relationship between reduced COMT function, anxiety and stress responsivity in mice. To compare the effect of acute vs. chronic restraint stress in female COMT KO vs. WT mice, serum corticosterone and cytokine concentrations were measured [Experiment 1]. Sensitivity to the benzodiazepines midazolam and chlordiazepoxide in the light-dark test was assessed in female COMT KO vs. WT mice [Experiment 2]. Effects of acute administration of the COMT inhibitor tolcapone, and of these same benzodiazepines thereon, in the light-dark test were assessed in female C57BL/6 mice [Experiment 3]. COMT KO mice demonstrated an increased corticosterone response to acute but not chronic stress, and a modified cytokine profile after chronic, but not acute stress. COMT KO mice showed increased anxiety, but benzodiazepine sensitivity was affected by COMT genotype. Whilst tolcapone had no effect on light/dark performance in C57BL6/J mice it decreased benzodiazepine sensitivity. These data elaborate earlier findings of increased anxiety in female COMT KO mice and also clarify a role for COMT in modulating stress-related hormonal and immune parameters in a manner that depends on chronicity of the stressor.
Article
ADHD is a major burden in adulthood, where co-morbid conditions such as depression, substance use disorder and obesity often dominate the clinical picture. ADHD has substantial shared heritability with other mental disorders, contributing to comorbidity. However, environmental risk factors exist but their interaction with genetic makeup, especially in relation to comorbid disorders, remains elusive. This review for the first time summarizes present knowledge on gene x environment (GxE) interactions regarding the dopamine system. Hitherto, mainly candidate (GxE) studies were performed, focusing on the genes DRD4, DAT1 and MAOA. Some evidence suggest that the variable number tandem repeats in DRD4 and MAOA may mediate GxE interactions in ADHD generally, and comorbid conditions specifically. Nevertheless, even for these genes, common variants are bound to suggest risk only in the context of gender and specific environments. For other polymorphisms, evidence is contradictory and less convincing. Particularly lacking are longitudinal studies testing the interaction of well-defined environmental with polygenic risk scores reflecting the dopamine system in its entirety.
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Key points  Exaggerated cardiovascular responses to stress increase risk for hypertension and cardiovascular disease, but the mechanisms controlling the magnitude of this response are not understood.  Catecholaminergic neurons located in the hindbrain area termed the nucleus of the solitary tract (NTS) modulate the control of blood pressure and are activated by psychological stress, but their role in modulating the cardiovascular response to stress is unknown.  In this study we lesioned these NTS catecholaminergic neurons and measured the cardiovascular and hormonal responses to psychological stress in rats.  We showed that lesioning these neurons increases baseline blood pressure and causes an exaggerated blood pressure response to acute or repeated psychological stress, suggesting that physiological or pathophysiological inhibition of these neurons could lead to exaggerated stress responses and hypertension.  These results help us understand the mechanisms that contribute to enhanced cardiovascular responses to psychological stress.
Article
BACKGROUND: The catechol-O-methyltransferase (COMT) gene val158met polymorphism (rs4680) has been found to be associated with various psychiatric phenotypes including panic disorder. Considering the probable genetic influence of COMT on the pathogenesis of panic disorder and white matter connectivity, the present study investigated white matter connectivity using diffusion tensor imaging in relation to the COMT genotype in panic disorder. METHODS: Twenty-six patients with panic disorder and twenty-six age- and gender-matched healthy controls participated in this study. Brain magnetic resonance scans and genotype analysis for COMT rs4680 were conducted. Panic Disorder Severity Scale, Albany Panic and Phobia Questionnaire, and Anxiety Sensitivity Inventory-Revised were assessed. Tract-based spatial statistics (TBSS) were used for image analysis. RESULTS: There was no significant difference in white matter analysis between panic disorder and healthy controls. However, TBSS analysis showed increased fractional anisotropy (FA) in posterior thalamic radiation, posterior and superior corona radiata, superior longitudinal fasciculus, and sagittal stratum, all located in the right hemisphere in COMT AA/AG genotype group compared to GG genotype in panic disorder. Voxelwise correlational analysis revealed the symptom severity scores are correlated with the FA in white matter tracts that previously showed significant group differences between AA/AG and GG genotypes in COMT AA/AG genotype group, while no significant correlation was found in GG genotype group. LIMITATIONS: The sample size in each group was small, hence, further studies with larger numbers of patients are needed to confirm our findings. CONCLUSIONS: These data suggested that COMT rs4680 could affect the white matter connectivity in panic disorder.
Chapter
Resilience has been defined as a dynamic process of maintaining positive adaptation and effective coping strategies in the face of adversity (Luthar et al. 2000). Although most scholars and members of the general public have an intuitive understanding of resilience, ambiguities in definition, measurement, and application contribute to scientific criticism regarding the usefulness of resilience as a theoretical construct (Kaplan 1999; Tolan 1996). Previous reviews have addressed ambiguities and limitations of the research literature with a focus on children and adolescents facing adversity (Luthar et al. 2000). These authors call for greater research attention on resilience at different points in human development. This chapter focuses on the definition, ambiguity, and application of the construct of resilience across the adult lifespan as it relates to successful aging (see Chap. 2). Other chapters throughout this book focus on various domains of resilience including genetic, physical, and personality (see Chaps. 3 and 6), emotional (see Chap. 5), creative (see Chap. 7), and spiritual (see Chap. 11). Our goal in this initial chapter is to describe and define resilience as it relates to older adults and to operationalize this construct across various domains. In so doing, we expand the critical review provided by Luthar et al. (2000) to adult development and aging. Additionally, we address three controversies evident in our review of the literature on the construct of resilience within adult development and aging.
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Nanoneuroscience is a new emerging discipline that seeks to solve certain hitherto intractable problems in the neurosciences using nanoscientific perspectives and tools. These state–of–the–art methods stand to meet some of the most challenging feats in neuroscience, such as finding better means of diagnosis, treatment, and prevention for various neurological, neurodevelopmental, and neuropsychiatric disorders. Nanotechnology is arguably one of the most optimal ways currently available to address the core essence of higher cognitive functions. A nanoscale emphasis on the mechanical interactions of biomolecules is uniquely capable of demonstrating the multiple ways in which neurons communicate and transmit signals, ranging from the traditional means of interneuronal and intraneuronal communication to novel modes of biomolecular computation. Notable milestones in nanoscience include the development of instruments and techniques enabling interactions with small surfaces or individual molecules, such as scanning tunneling microscopy (STM), atomic force microscopy (ATM), and nanotweezers. These tools operate in the nanometer size range and have the potential to reveal details about molecular events and subcellular operations within neurons. Nanoscientists have also developed a wide variety of nanomaterials – carbon nanotubes, nanoparticles, nanowires, and quantum dots, among others – that can be used to probe and stimulate neurons or parts of neurons. Nanoparticle–based drug delivery systems (or gene therapy delivery systems) showing enhanced ability to cross the blood–brain barrier could potentially be used to treat a number of neurological, neurodevelopmental, and neuropsychiatric diseases. Nanomaterials, used alone and in hybrid combinations with other materials, can be used to diagnose nervous system disorders, to measure neurotransmitter levels or electrical activity in discrete brain sites, to stimulate discrete brain sites, and finally, to build potential nanoscale prosthetic devices that restore normal neural activity patterns and cognitive function.
Article
The catechol-O-methyltransferase (COMT) val158met single nucleotide polymorphism (SNP) alters metabolic activity of the COMT enzyme regulating catecholamines, with the Val (valine) allele resulting in 40% greater enzymatic activity than the Met (methionine) allele. Previous research has identified systematic inter-individual differences in cognitive and behavioral phenotypes related to this polymorphism, often attributed to the fact that extracellular dopamine in the prefrontal cortex is strongly affected by the COMT enzyme. The neurophysiological mechanisms mediating these inter-individual differences in specific brain systems and task contexts remain to be established however. In the current study, we examined the extent to which physio-mechanistic differences by COMT genotype affect somato-visceral and visual cortical responses to learned threat cues. Classical aversive differential conditioning was implemented using rapidly phase-reversing grating stimuli, previously shown to engage retinotopic visual cortex. Differential response patterns in sensory and autonomic systems were elicited by pairing one grating (CS+, conditioned stimulus), but not the other (CS-), with a noxious stimulus. Dense-array electroencephalography and somato-visceral measures of defensive reactivity were recorded in addition to self-report data. Individuals of the Val/Val genotype, compared to Met allele carriers, reliably showed greater initial enhancement in their visuocortical response to the CS+, accompanied by stronger defensive engagement, indexed by heart rate acceleration and startle potentiation. The finding that COMT polymorphism status affects threat cue reactivity at the visuocortical level is consistent with the notion that sensory processing of threat is facilitated by strong re-entrant bias signals from anterior areas, including the prefrontal cortex.
Article
Objectives: Many studies have reported an association of the COMT Val158Met polymorphism and major depressive disorder (MDD), although with conflicting results. The role of gender is a possible modulator. To overcome the problem of poor sample size detecting genes of small effect, we perform a meta-analysis of the current literature, investigating the influence of the COMT Val158Met polymorphism on the pathogenesis of MDD, with a major focus on the effect of gender. Methods: Out of 977 retrieved articles, 21 included case-control studies allowed the analysis of 9005 patients with MDD and 12,095 controls. Allelic and genotypic pooled odds ratios (OR) were calculated for the total sample and gender-subgroups. Results: In the absence of publication bias, allelic and genotypic analyses showed no significant association in the total sample, as well as in gender-specific subgroups. Sensitivity analysis did not alter the ORs. Conclusions: The results imply a complex nature of the genotype × phenotype interaction. Further studies of the COMT gene or the locus remain to be justified given the important positional and functional relevance and the plethora of gender-specific findings. A possible way to further dissect this topic is shifting the focus to gene-based or genome-wide analyses of intermediate phenotypes.
Article
Lay summary: Our results showed no evidence of significant association of either COMT rs4680 or 5-HTT 5-HTTLPR variants with ASD, showing that these two genes may not be major susceptible genetic factors in ASD occurrence, and may have a reciprocal action with each other in combination with environmental factors. These findings further provide evidence that a single gene variant may not dictate autism occurrence, but possibly contributes to a specific phenotype or subtype of ASD.
Chapter
Rigid motivational appraisals (i.e., demandingness) are core processes in emotional disorders. In this chapter, I suggest that rigid motivational appraisals result in disturbed emotions when they are based on embodied representations that recruit abnormal motivational states. I review studies that support the idea that rigid motivational appraisals involve the understanding of the significance of negative events based on simulations in a hyper-reactive mesolimbic dopamine motivational system. The concept of embodied rigid appraisals integrates research from human and nonhuman animal models in the support of rigid appraisals as a core process for emotional psychopathology. I suggest that embodied rigid appraisals are markers of behavioral inflexibility phenotype in response to stress that result in emotional disorders. Based on this understanding, the processes of development, maintenance, and the methods of change that target disturbed motivation and inflexible coping can be used to understand the development and change of rigid thinking.
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Genetic variants that regulate hypothalamic–pituitary–adrenal (HPA) axis function have been demonstrated to moderate the association between parenting and mental health. However, extant research has focused primarily on (i) effects of individual genes or (ii) maternal as opposed to paternal parenting. Using a multilocus genetic profile score (MGPS) approach, the current study is the first to examine the moderation effect of multilocus HPA-axis related genetic variants on the association of both maternal and paternal parenting with adolescent internalizing and externalizing symptoms. In a sample of 772 Chinese Han adolescents ( M age = 16.48 ± 1.40 years; 50.1% girls), a theory-driven MGPS was calculated using six polymorphisms within HPA-axis related genes ( CRHR1 , NR3C1 , NR3C2 , FKBP5 , COMT , and HT1RA ). Results showed that the MGPS interacted with both maternal and paternal parenting in the association with adolescent internalizing symptoms, but not externalizing symptoms. Consistent with the differential susceptibility model, adolescents with high versus low MGPS exhibited not only more internalizing symptoms when exposed to low quality of parenting but also less internalizing symptoms when exposed to high quality of parenting. The current findings highlight the potential value of using a multilocus approach to understanding gene-by-environment interaction (G×E) effects underlying mental health. Within such G×E effects, not only maternal but also paternal parenting should be addressed.
Article
Catecholamines modulate endocrine stress reactivity by affecting regulatory influences of extra-hypothalamic brain structures on hypothalamus-pituitary-adrenal (HPA)-axis. Therefore, we aimed to investigate combined effects of functional allelic variations that affect dopamine availability in both cortical (COMT Val¹⁵⁸Met polymorphism) and subcortical (DAT1 VNTR) brain regions on HPA-axis reactivity to psychosocial stress. By using a standardized laboratory stress task (public speaking) we obtained saliva cortisol samples during stress exposure and an extended recovery period in 100 healthy male adults. We report for the first time significant epistasis between COMT Val¹⁵⁸Met and DAT1 VNTR on cortisol response patterns. Subjects homozygous for both the Met¹⁵⁸ and the 10-repeat allele of DAT1 VNTR were characterized by markedly elevated cortisol reactivity and impaired stress recovery compared to all other groups. Our results indicate a crucial role of functional genetic variants within the dopaminergic system in the modulation of HPA-axis response patterns and highlight the need to investigate combined effects of specific candidate genes on stress-related endophenotypes.
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Background Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. Results We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood – the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. Conclusion Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.
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Recent efforts to integrate psychometric and neurobiological data about personality have stimulated diverse interdisciplinary applications. The dissociation of major brain systems linked to procedural and propositional memory and learning has clarified the clinical distinction between two components of personality: temperament and character. Temperament can be defined in terms of individual differences in percept-based habits and skills (i.e. related to procedural memory and learning), which are regulated by the amygdala, hypothalamus, striatum, and other parts of the limbic system. In contrast, character can be defined in terms of individual differences in concept-based goals and values (i.e. related to propositional memory and learning), which are encoded by the hippocampal formation and cerebral neocortex. Recent descriptive, developmental, genetic, and neurobehavioral studies indicate that at least four dimensions of temperament and three dimensions of character can be uniquely described and functionally dissociated.
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Quantitative genetic research has built a strong case for the importance of genetic factors in many complex behavioral disorders and dimensions in the domains of psychopathology, personality, and cognitive abilities. Quantitative genetics can also provide an empirical guide and a conceptual framework for the application of molecular genetics. The success of molecular genetics in elucidating the genetic basis of behavioral disorders has largely relied on a reductionistic one gene, one disorder (OGOD) approach in which a single gene is necessary and sufficient to develop a disorder. In contrast, a quantitative trait loci (QTL) approach involves the search for multiple genes, each of which is neither necessary nor sufficient for the development of a trait. The OGOD and QTL approaches have both advantages and disadvantages for identifying genes that affect complex human behaviors.
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This paper describes a protocol for induction of moderate psychological stress in a laboratory setting and evaluates its effects on physiological responses. The 'Trier Social Stress Test' (TSST) mainly consists of an anticipation period (10 min) and a test period (10 min) in which the subjects have to deliver a free speech and perform mental arithmetic in front of an audience. In six independent studies this protocol has been found to induce considerable changes in the concentration of ACTH, cortisol (serum and saliva), GH, prolactin as well as significant increases in heart rate. As for salivary cortisol levels, the TSST reliably led to 2- to 4-fold elevations above baseline with similar peak cortisol concentrations. Studies are summarized in which TSST-induced cortisol increases elucidated some of the multiple variables contributing to the interindividual variation in adrenocortical stress responses. The results suggest that gender, genetics and nicotine consumption can influence the individual's stress responsiveness to psychological stress while personality traits showed no correlation with cortisol responses to TSST stimulation. From these data we conclude that the TSST can serve as a tool for psychobiological research.
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The levels of activity of human erythrocyte (RBC) catechol-O-methyl-transferase (COMT) and human plasma dopamine-β-hydroxylase (DBH) are inherited in a monogenic fashion. The COMT in erythrocytes of subjects homozygous for the allele for low basal enzyme activity, COMTL, is more thermolabile than that in the erythrocytes of subjects with genetically high basal enzyme activity. This observation suggests that the locus COMT may represent the structural gene for COMT in man. Wide individual variations in the thermal stability of human plasma DBH also occur. There is a significant familial aggregation of the trait of thermolabile plasma DBH. Although subjects with thermolabile plasma DBH have average basal plasma DBH activity only about 55% of that of subjects with thermostable enzyme, the trait of thermolability does not cosegregate with DBHLL, the allele for very low basal plasma DBH activity. Studies of thermal stability may help to increase our understanding of the biochemical basis of the genetic regulation of catecholamine enzymes in man.
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One of the major neurobiological alterations in depressive disorders consists in a disturbed regulation of the hypothalamic-pituitary-adrenocortical (HPA) system. This is reflected by a pathological increase in the adrenocorticotropin (ACTH) and cortisol release after pretreatment with 1.5 mg dexamethasone (DEX) the previous night and a challenge with 100 micrograms corticotropin-releasing hormone (CRH) the next day. The changes evoked by this combined DEX-CRH test recede partially with an improvement of the psychopathological symptoms of depressed patients. It is still unclear, however, whether this long-lasting disturbance of the HPA system is due to acquired changes in the acute illness or whether it plays a causal role and could be considered as a trait or vulnerability marker for depression. In a previous study we have examined the HPA function of healthy probands with a high genetic load for affective disorders. We found that this group of high-risk probands (HRPs) showed abnormal DEX-CRH test results with a cortisol release that was between that of a control group and a group of patients with depression. In a follow-up study we now reexamined 14 of the 47 HRPs about 4 years after the index investigation and found surprisingly constant DEX-CRH test results, so that one of the requirements for a vulnerability marker is fulfilled.
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The administration of a Dutch version of the Spielberger State-Trait Anxiety Inventory to medical students has been described. In Study 1 a significant negative relationship was obtained between level of anxiety and level of academic success. In Study 2 these results were partly replicated. Besides data obtained with the Dutch version in an anxiety-provoking situation and test-retest reliabilities, support was given to the Spielberger theory of trait-state anxiety by demonstrating that the increase in A-State level is higher for the group of high A-Trait men than for the group of low A-Trait students.
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Low catechol-O-methyltransferase (COMT) activity (less than 8 units per milliliter) in the human erythrocyte is inherited as an autosomal recessive trait (COMTL). The average half-life of COMT in erythrocyte lysates incubated at 48 degrees C was significantly shorter in lysates from three subjects with low enzyme activity than in lysates from three subjects with high enzyme activity (12.5 +/- 0.9 minutes compared with 21.2 +/- 1.4 minutes, P less than .01). When the ratios of COMT activities in lysates heated at 48 degrees C for 15 minutes to enzyme activities in unheated samples were used as a measure of enzyme thermostability in blood samples from 316 randomly selected subjects, the ratios were significantly less for subjects with low enzyme activity than for subjects with higher enzyme activity. The presense of thermolabile COMT in blood of individuals homozygous for COMTL raises the possibility that the locus COMT may represent the structural gene for the human enzyme.
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Catechol-O-methyltransferase activity and thermal stability in the human red blood cell are controlled by a common genetic polymorphism. Approximately 25% to 30% of a randomly selected population sample is homozygous for the traits of low catechol-O-methyltransferase activity and thermolabile enzyme in the red blood cell. We tested the hypothesis that the catechol-O-methyltransferase genetic polymorphism might also control those same characteristics of the enzyme in an important human drug-metabolizing organ, the liver. Catechol-O-methyltransferase enzyme activity and thermal stability were measured in 99 hepatic biopsy samples obtained during clinically indicated surgery. The frequency distribution of heated/control ratios, a measure of enzyme thermal stability, was bimodal, with 28% of samples included in a subgroup with thermolabile enzyme. There were no sex-related differences in hepatic catechol-O-methyltransferase thermal stability. However, catechol-O-methyltransferase enzyme activity in hepatic tissue from male subjects was significantly higher than that in samples from female subjects: 61.3 +/- 20.2 units/mg protein (mean +/- SD; n = 50) versus 46.6 +/- 22.2 units/mg protein (n = 49; p = 0.0002). There was a significant correlation of hepatic catechol-O-methyltransferase activity and thermal stability in samples from both female (rs = 0.698; p = 0.0001) and male subjects (rs = 0.429; p = 0.002). Finally, when both red blood cell catechol-O-methyltransferase activity and thermal stability were measured in blood samples from 34 of these patients, there was a significant correlation between catechol-O-methyltransferase heated/control ratios and levels of enzyme activity in hepatic tissue and in red blood cell lysates. These findings indicate that the genetic polymorphism that controls catechol-O-methyltransferase activity level and thermal stability in red blood cells also controls those same properties of the enzyme in the human liver.