Catechol-O-methyltransferase polymorphism (COMT) in suicide attempters A possible gender effect on anger traits.код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:1042 –1047 (2007) Catechol-O-Methyltransferase Polymorphism (COMT) in Suicide Attempters: A Possible Gender Effect on Anger Traits Patrick Baud,1 Philippe Courtet,2,3 Nader Perroud,1 Fabrice Jollant,2,3 Catherine Buresi,1 and Alain Malafosse1,3,4 1 Department of Psychiatry, University Hospital of Geneva, Geneva, Switzerland Department of Psychological Medicine and Psychiatry, CHU Montpellier, France 3 INSERM E 361, Montpellier, France 4 Department of Medical Genetics and Development, School of Medicine, Geneva, Switzerland 2 Anger-related personality traits are considered contributory risk factors for suicidal behavior. According to twin studies, they are partially under genetic control and their various clinical expressions have been associated with serotonergic and catecholaminergic activities. A functional polymorphism on the human catechol-O-methyltransferase (COMT) gene, which codes for the catecholamines inactivating enzyme COMT, has been shown to influence aggressive and angerrelated traits in various clinical populations. The aim of the present study was to investigate the association between anger traits (as characterized by the State-Trait Anger Expression Inventory, STAXI) and COMT Val158Met polymorphism in suicide attempters (n ¼ 427) and control subjects (n ¼ 185). Results showed that the high activity genotype (Val/Val) was more frequent in suicide attempters than in normal controls. Moreover, the Val/Val genotype markedly affected the scores on two STAXI subscales—Trait Anger and Anger Control—in female suicide attempters, thus suggesting a possible gender effect of the COMT genotype on a stable personality trait. These results are discussed in the light of recently published data on the effect of COMT Val158Met polymorphism on different cognitive and behavioral traits. ß 2007 Wiley-Liss, Inc. KEY WORDS: suicidal behavior; COMT gene; anger-related personality traits Please cite this article as follows: Baud P, Courtet P, Perroud N, Jollant F, Buresi C, Malafosse A. 2007. Catechol-O-Methyltransferase Polymorphism (COMT) in Suicide Attempters: A Possible Gender Effect on Anger Traits. Am J Med Genet Part B 144B:1042–1047. Grant sponsor: Swiss National Foundation; Grant numbers: 32102168.03, 32-112084. *Correspondence to: Patrick Baud, M.D., Department of Psychiatry, Clinique de Belle-Idée, 2 chemin du Petit-Bel-Air, 1225 Chêne-Bourg, Switzerland. E-mail: firstname.lastname@example.org Received 11 October 2006; Accepted 6 March 2007 DOI 10.1002/ajmg.b.30541 ß 2007 Wiley-Liss, Inc. INTRODUCTION Anger-related personality traits are considered contributory risk factors for suicidal behavior and may partially be under genetic control. Indeed, a genetic contribution in anger-related traits is suggested by the results of a twin study investigating sibling similarity in angry aggression and irritability [Gustavsson et al., 1996] and—for trait anger specifically—by a study of middle-aged male twins [Sluyter et al., 2000]. Most studies on suicidal behavior investigated the synergy of aggression and anger-related traits with impulsivity traits, the interactions between these sets of behavioral dispositions being complex and poorly disentangled [Apter et al., 1990; Apter et al., 1993; Horesh et al., 1997; Critchfield et al., 2004; Baud, 2005; Ramirez and Andreu, 2006]. Anger and the related construct of hostility-aggression are thought to be associated with serotonergic as well as catecholaminergic activities. Although, catecholamine-related genes have been less investigated than serotonin-related genes in suicidal behavior, the well-established link between aggressive and suicidal behaviors make them important candidate genes for suicide studies. Catechol-O-methyltransferase (COMT) is a major enzyme involved in the inactivation of catecholamines, including adrenaline, noradrenaline, and dopamine. A common functional polymorphism (a G to A substitution at codon 158 that results in a change of amino acid from valine (Val) to methionine (Met) of the human COMT gene) has been identified [Lachman et al., 1996], the Met allele being associated with a lower enzymatic activity than the Val allele. In fact, homozygosity for the Met allele yields a threefold to fourfold reduction in COMT enzymatic activity relative to Val homozygotes [Weinshilboum et al., 1999; Shield et al., 2004]. The Val allele leads to a more efficient degradation of dopamine and to lower prefrontal dopamine levels. Associations have been reported between the COMT Val158Met genotype and aggression in schizophrenic subjects. Most studies found the Met allele to be associated with various measures of aggression in schizophrenia [Strous et al., 1997; Lachman et al., 1998; Kotler et al., 1999; Han et al., 2004], although one study reported an association between the Val/ Val genotype and increased aggression [Jones et al., 2001]. Subsequent work from the same group failed to confirm this result on a new sample of schizophrenic patients [Zammit et al., 2004]. Another study on Chinese schizophrenic patients failed to find an association between schizophrenia, violence or suicide, and the COMT Val158Met polymorphism [Liou et al., 2001]. There are few genetic association studies on the COMT genotype with either suicidal behavior or anger-related traits COMT Polymorphism in Suicide Attempters in non-psychotic clinical populations. An investigation on a small sample of patients did not find any association between suicidal behavior or ideation and COMT Val158Met genotype or allele frequencies [Russ et al., 2000]. In contrast with this report, Nolan et al.  found a significant association between the COMT Val158Met genotype and a history of violent suicide attempts in two samples of schizophrenic and schizoaffective patients: the Met allele was more frequent in male (but not female) subjects who had attempted suicide by violent means. A recent study on a Japanese population also reported a lower frequency of the Val/Val genotype in male suicide completers than in male controls, allowing the authors to suggest that this genotype could protect against suicide [Ono et al., 2004]. Finally, the influence of COMT Val158Met polymorphism was examined on both phenotypes—suicidal behavior and anger-related personality traits—in two samples of suicide attempters and control subjects [Rujescu et al., 2003]. The authors reported no overall difference in allele/genotype frequencies between suicide attempters and controls, but they described a complex picture regarding anger traits, where carriers of the Met/Met genotype expressed their anger more outwardly whereas carriers of the Val/Val genotype expressed it more inwardly and reported more state anger. In summary, encouraging but still contradictory results have been gained from association studies on suicidal behavior and anger-related traits with the COMT gene. The first aim of the present study was to investigate whether the COMT Val158Met polymorphism was associated with anger-related personality traits in suicide attempters. Another related objective was to explore the relationships between anger traits and COMT Val158Met genotypic distribution in a non-clinical sample of unrelated subjects. Control subjects recruited in a Blood Donor Center were compared with suicide attempters for their scores on the subscales of the State-Trait Expression Inventory and for COMT genotype distributions and allele frequencies. 1043 unit. Suicide attempts were classified as violent according to the criteria proposed by Asberg et al. . Anger-related traits were assessed using the State-Trait Anger Expression Inventory (STAXI; Spielberger 1988). The STAXI is a 44-item self-report questionnaire measuring the experience and expression of anger, in accordance with the state-trait personality theory [Eckhardt et al., 2004]. The experience of anger comprises State Anger (the current feelings experienced by an individual) and Trait Anger (the individual disposition to experience anger or the ease, frequency and intensity of becoming angered), whereas the expression of anger comprises the three components of Anger-In (which measures the tendency of an individual to suppress angry feelings), Anger-Out (the tendency to outwardly express anger towards people or objects), and Anger control (the capacity of an individual to regulate or control his/her anger). Genotyping COMT Val158Met (G/A nucleotide or high and low activity, respectively) genotyping was carried out according to the following protocol: PCR was done in a 25 ml volume with 100 ng DNA, 10 pmol primers COMTF (TCACCATCGAGATCAACCCC) and COMTR (ACAACGGGTCAGGCATGC), 200 nM DNTP, 1.2 mM MgCl2, 1 U Taq polymerase (Eurobio, Brunschwig, Basel, Switzerland). Temperature annealing was 628C and elongation was 30 sec at 728C. The 96 bp PCR product was cut by 5 U Nla III (Biolabs, Bioconcept, Allschwil, Switzerland) and run on Spreadex EL 400 gel (Elchrom Scientific, Cham, Switzerland) for 75 min at 120 V or on a 10% acrylamide gel (19/1) in 0.5X TBE for 150 min at 250 V. After coloration with ethidium bromide and visualization under UV, Val allele give a non-cut 83 bp fragment and Met allele two fragments, a 65 and 18 bp. A 13 bp fragment was constantly present after digestion. Statistical Analyses MATERIALS AND METHODS Subjects Suicidal patients were recruited from the University Hospitals of Geneva (Switzerland) and Montpellier (France). Swiss patients (n ¼ 107; 63.6% females) were recruited on the basis of a past history of a suicide attempt, without considering whether suicidal behavior was or was not the immediate reason for hospitalization, whereas French patients (n ¼ 320; 73.1% females) were included in the study shortly after having made a suicide attempt. Control subjects (n ¼ 185, 29.7% females) were recruited from the Blood Donor Center of the University Hospital of Geneva. All subjects were between 18 and 75 years old, French speaking, and with all four biological grandparents originating from Western European countries. Subjects with a neurological disorder were not included. After a complete description of the study had been given to the subjects, written informed consent was obtained. The two populations of suicide attempters were compared across demographic and clinical characteristics using Chisquare and t-tests. Differences in genotype and allele frequencies between French and Swiss samples of suicide attempters were analyzed using the Chi-square test. An univariate analysis of variance (ANCOVA) was used to investigate the effect of each genotype on subscales of the STAXI. Analyses were controlled for age, sex and suicidal behavior. The covariate age was included because French suicide attempters were younger than the Swiss ones (38 vs. 40.9, P ¼ 0.042) and gender was added because of a higher number of women among suicide attempters. Furthermore, suicidal behavior was added as a covariate in the analysis of the whole population (comprising suicide attempters and control subjects without suicide attempt). When the effect of the genotype on a subscale of the STAXI was statistically significant, ANCOVA was followed by a non-parametric test (Kruskal–Wallis (KW)) to take into account the nonparametric distribution of the STAXI subscales. Analyses used a two-tailed estimation of significance, and a level of P < 0.05 was considered statistically significant. Statistical package SPSS V.11.0 was used. Psychiatric and Behavioral Assessments Patients and control subjects were assessed for psychiatric diagnoses using the French version of the Diagnostic Interview for Genetic Studies [Nurnberger et al., 1994]. A suicide attempt was defined as intentional self-harm that was not selfmutilatory in nature [Mann, 2003] and required medical evaluation and treatment in an emergency or intensive care RESULTS Clinical and demographic data of suicide attempters and control subjects are presented in Table I. The COMT Val158Met polymorphism was in Hardy–Weinberg equilibrium for clinical and control populations (0.91 and 0.3, respectively) (Table II). 1044 Baud et al. TABLE I. Clinical and Demographic Data of Suicide Attempters (SAs) and Control Subjects n (%) Suicide attempters (n ¼ 427) Control subjects (n ¼ 185) French SAs (n ¼ 320) Swiss SAs (n ¼ 107) 302 (70.7) 125 (29.3) 55 (29.7) 130 (70.3) 234 (73.1) 86 (26.9) 68 (63.6) 39 (36.4) 285 (66.7) 64 (15) 29 (6.8) 6 (1.4) 6 (1.4) 9 (2.1) 10 (2.3) 2 (0.5) 16 (3.7) 36 (19.5) 1 (0.5) 3 (1.6) 0 5 (2.7) 0 15 (8) 125 (67.6) 0 239 (74.7) 29 (9.1) 23 (7.2) 5 (1.6) 5 (1.6) 0 3 (0.9) 2 (0.6) 14 (4.4) 46 (43) 35 (32.7) 6 (5.6) 1 (0.9) 1 (0.9) 9 (8.4) 7 (6.5) 0 2 (1.9) 244 (76.3) 75 (23.4) 1 (0.3) 68 (63.6) 33 (30.8) 6 (5.6) Gender Female Male Diagnosis MDD BP1 BP2 BP nos Dysthymia SZ þ SAD Others No diagnosis Unknown Suicide attempt Non-violent Violent Unknown Age Mean (SD) 312 (73.1) 108 (25.3) 7 (1.6) 0 0 38.7 (12.8) 46.08 (12.8) 37.99 (13.6) 40.89 (9.9) MDD: major depressive disorder; BP1: bipolar disorder type 1; BP2: bipolar disorder type 2; BP nos: bipolar disorder not otherwise specified; SZ: schizophrenia; SAD: schizoaffective disorder. TABLE II. Genotype Distributions and Allele Frequencies of the COMT Val158Met Polymorphism in Suicide Attempters (SAs) and Control Subjects (C) Allele frequencies, n (%) Genotype distributions, n (%) SAs (n ¼ 427) C (n ¼ 185) Val/Val Val/Met Met/Met P; w2 Val Met P; w2 124 (29) 34 (18.4) 218 (51.1) 107 (57.8) 85 (19.9) 44 (23.8) 0.021; 7.72 466 (54.6) 175 (47.3) 388 (45.4) 195 (52.7) 0.019; 5.47 Genotype and Allele Distributions in Suicide Attempters and Control Subjects COMT Val158Met Genotype Effect on Anger Traits COMT Val158Met genotype and allele distributions differed significantly between suicide attempters (n ¼ 427) and control subjects (n ¼ 185): suicide attempters have a higher frequency of the Val/Val genotype than control subjects (29% vs. 18.4%; P ¼ 0.021), as well as a higher Val allele frequency (54.6% vs. 47.3%; P ¼ 0.019) (Table II). There was no difference between non-violent and violent suicide attempters, nor between French and Swiss suicide attempters (data not shown). After controlling for age and sex, an effect of COMT Val158Met genotype distribution on various anger-related traits was found in the whole population (controls and suicide attempters): State Anger and Trait Anger scores appeared significantly higher for the subjects with the high-activity Val/Val genotype than for those carrying the Val/Met and Met/Met genotype, whereas Anger Control scores were significantly lower (Table IV). However, there were no more significant differences in any of the subscales between the genotypes when suicide attempt was taken as a confounding variable (Table IV). Indeed, while the COMT Val158Met genotype modulates various anger-related traits in suicide attempters, this effect was not observed in controls. Moreover, this effect remains the STAXI Scores The population of suicide attempters showed significantly different STAXI scores on each subscale compared with control subjects (Table III). TABLE III. STAXI Subscales Scores in Suicide Attempters and Control Subjects STAXI subscale State anger Trait anger Anger in Anger out Anger control Suicide attempters (n ¼ 427) Control subjects (n ¼ 185) Mean (SD) Mean (SD) P; t-test 20.2 (7.2) 23.7 (6) 21.1 (5) 16.5 (5) 21.3 (4.9) 13.2 (4.4) 19.4 (4.9) 15.8 (4.5) 12.3 (3.2) 24.6 (4.1) <0.001; 12.2 <0.001; 8.5 <0.001; 12.5 <0.001; 10.4 <0.001; 8.1 COMT Polymorphism in Suicide Attempters 1045 TABLE IV. Scores for State-Trait Anger Expression Inventory (STAXI) Subscales as a Function of COMT Val158Met Genotype in Suicide Attempters and Control Subjects (n ¼ 612) Adjusted for SA Genotype STAXI subscale Val/Val (n ¼ 158) Val/Met (n ¼ 325) Met/Met (n ¼ 129) F df P KW (P; df; w2) State anger Trait anger Anger-in Anger-out Anger Control 19.7 (7.5) 23.5 (6.2) 19.5 (5.4) 15.9 (5.4) 21.4 (5.3) 17.7 (7.2) 22.4 (5.9) 19.6 (5.4) 15.2 (4.8) 22.7 (4.8) 17.1 (6.5) 21 (6.1) 19.4 (5.6) 14.4 (4.7) 23.4 (4.4) 3.99 3.68 0.03 1.53 4.47 2/605 2/605 2/605 2/605 2/605 0.019 0.026 0.97 0.22 0.012 0.002; 2; 12.82 0.003; 2; 11.36 0.001; 2; 13.03 F df P 1 1 1 0.21 1.14 2/599 2/599 2/599 2/599 2/599 0.368 0.369 0.366 0.812 0.321 Data are presented as mean (SD). same after controlling for sample origin. After pooling French and Swiss suicide attempters (as there was no difference in the COMT Val158Met genotype distribution) and taking into account sex and age as confounding variables, Trait Anger scores were found to be significantly higher and Anger Control scores significantly lower in suicide attempters carrying the Val/Val genotype than in those carrying the Val/Met or Met/ Met genotypes (Trait Anger: P ¼ 0.003; KW: P ¼ 0.001; Anger Control: P ¼ 0.036; KW: P ¼ 0.003) (Table V). The effect of the COMT Val158Met genotype on Trait Anger was still significant in the subgroup of violent suicide attempters (P ¼ 0.013, F ¼ 4.5, df ¼ 2/101; KW: P ¼ 0.018, w2 ¼ 8.01, df ¼ 2). The effect of COMT Val158Met could be mostly accounted for by the female population, which represents more than 70% of the SA group. Indeed, gender plays an important role in the effects of the COMT Val158Met genotype on STAXI subscales scores. Scores for Trait Anger were significantly higher (P ¼ 0.002, F ¼ 6.26, df ¼ 2/298, KW: 0.002; df ¼ 2; w2 ¼ 12.55) and scores for Anger Control significantly lower (P ¼ 0.003, F ¼ 4.98, df ¼ 2/298, KW: P ¼ 0.002, df ¼ 2, w2 ¼ 12.8) in female suicide attempters carrying the high-activity Val/Val genotype. It should be noted that the subgroup of violent female SAs, in spite of its small size, contributed significantly to the global genotypic and allelic influences of the high-activity COMT variant on Trait Anger scores in the whole female population of SAs, as indicated by the following data: nonviolent female SAs (n ¼ 240): P ¼ 0.04 and KW 0.03; violent female SAs (n ¼ 58): P ¼ 0.046 and KW 0.051. The effect of the high-activity COMT genotype on Trait Anger is specific to female gender, as there is no such difference in male suicide attempters. DISCUSSION Here, we report an association between the COMT Val158Met genotype and anger-related personality traits in suicidal behavior. In our population, this association was genderspecific: female suicide attempters homozygous for the Val allele displayed higher scores on Trait Anger and lower scores on Anger Control, whatever the nature of the suicidal gesture, than female suicide attempters carrying a Met allele. Moreover, violent suicide attempters with the Val/Val genotype also showed a significantly elevated score on Trait Anger, which could partly be due to the sample of female violent suicide attempters. Finally, the modest but significant effect of the Val/Val genotype on State Anger, Trait Anger and Anger Control found in the whole population of suicide attempters and control subjects was exclusively accounted for by the sample of suicide attempters. It is noteworthy, however, that the smaller number of men than women and violent suicide attempters than non-violent cases, as well as the smaller number of controls than cases, might partly explain these results. While adding to the existing data set on the influence of the COMT gene on anger and aggressive personality traits, our findings are in apparent contradiction with the results of most association studies, where aggressive behaviors and angerrelated personality traits were linked to the Met variant. Several factors could account for these contradictory results. First, the inconsistencies may be due to the specific clinical characteristics of the populations under scrutiny: among the few studies reporting an association between the Met genotype/allele and violent suicide, one relates to schizophrenia patients [Nolan et al., 2000], whereas there were almost no schizophrenic patients included in our samples of suicide attempters (Table I). In schizophrenia studies the Met genotype/allele was mainly found associated with aggressive behaviors rather than with suicidal behavior. In fact, the association reported between violent suicidal behavior and the Met genotype/allele in the Nolan et al. study could be due to the co-presence in their schizophrenic patients of other-directed violent and aggressive behaviors, an overlapping phenotypic characteristic present in the majority of their clinical population. Moreover, cognitive disturbances have been repetitively associated with the Val genotype-allele, in schizophrenia, and more recently also in non-clinical populations. Indeed, lower performances on prefrontal executive cognition and working TABLE V. Scores for State-Trait Anger Expression Inventory (STAXI) Subscales as a Function of COMT Val158Met Genotype in Suicide Attempters (n ¼ 427) Genotype STAXI subscale Val/Val (n ¼ 124) Val/Met (n ¼ 218) Met/Met (n ¼ 85) F df P State anger Trait anger anger-in Anger-out Anger control 21.2 (7.4) 25.1 (5.6) 20.9 (4.8) 17.1 (5.2) 20.4 (5) 19.8 (7.3) 23.7 (5.9) 21.3 (4.9) 16.5 (4.9) 21.2 (4.7) 19.5 (6.4) 21.6 (6.5) 21.1 (5.4) 15.5 (5) 22.7 (4.7) 1.09 6 0.03 1.43 3.36 2/420 2/420 2/420 2/420 2/420 0.34 0.003 0.97 0.24 0.036 Data are presented as mean (SD). KW (P; df; w2) 0.001; 2; 14.57 0.003; 2; 11.85 1046 Baud et al. memory tasks have been associated with the Val variant [Egan et al., 2001; Malhotra et al., 2002]. These cognitive disturbances could also play a role in suicidal behavior in schizophrenic patients. Another study reporting an association between suicide and the Met allele [Ono et al., 2004] focused on completed suicide, whereas we studied suicide attempts. Most cases in the Ono et al. study were classified as violent suicides, but the clinical backgrounds of the suicide completers could not be obtained. There are some arguments to support the view that the clinical phenotype(s) of suicide attempt(s) may well differ from the phenotype(s) of suicide completion [Muller-Oerlinghausen and Roggenbach, 2002; Mann, 2003] and therefore both may depend on specific and partly different vulnerability genes. If this was the case, extrapolation from one clinical population to the other could become hazardous. However, these critical remarks could not explain the discrepancies between our results and those of [Rujescu et al., 2003], as both studies investigate the same COMT Val158Met polymorphism and relate on the STAXI scale to characterize anger traits in suicide attempters and control subjects. These authors reported no overall difference in COMT Val158Met allele/genotype frequencies between suicide attempters and controls, but they found a difference regarding the expression of anger: subjects with the Met/Met genotype expressed their anger more outwardly whereas the Val/Val genotype carriers expressed it more inwardly and reported more state anger. They concluded that the COMT Val158Met polymorphism may modify the phenotype of suicide attempts and anger-related traits, a conclusion that our data do not confirm. It is worth mentioning that the STAXI subscale scores found in our whole sample (suicide attempters plus controls) are far higher than those in the Rujescu et al. study (e.g. Trait Anger scores in subjects with the Val/Val genotype were 23.5 in our sample, versus 17.3 in the Rujescu et al. study. Scores for the low-activity genotype were respectively 21 and 17.5). The discrepancies between the results of the two studies may be explained by the size of the samples and the STAXI scores: being of a greater size and having higher Trait Anger scores (and lower Anger Control scores), our sample may be more sensitive to detect a genetic effect. Beside the commonly proposed reasons for contradictory results in genetic association studies—the nature of the associated psychiatric disorders, the effect of population stratification, and the lack of statistical power—these discrepancies may possibly find an explanation in the light of a recent study showing that haplotypes containing either the Val or the Met variant could influence a given phenotype (extraversion in the case) in the same direction [Stein et al., 2005]. Thus, Val allele as well as Met allele could exert a same phenotypic effect according to their haplotypic configuration. This aspect warrants new investigations. Interestingly, in the study by Stein et al. , the genetic associations to COMT were confined to women (either from a single polymorphism or from a haplotype perspective), a result already reported in a study on harm avoidance [Enoch et al., 2003]. Furthermore, several studies, although yielding contradictory results, have found associations of panic disorder and the COMT Val158Met genotype in women specifically [Domschke et al., 2004; McGrath et al., 2004; Woo et al., 2004] and preclinical data suggest that COMT variants could produce sexually dimorphic effects on catecholamine metabolism [Huotari et al., 2002]. These discrepancies may also be explained by the fact that all these studies do not take into account gene x environment interaction. Recently, Thapar et al.  showed that Val/Val genotype and lower birth weight interact to increase symptoms of conduct disorders in patients with attention-deficit/hyperactivity disorder. Interestingly, restricted fetal growth has also been shown to be a risk factor for suicide attempt [Mittendorfer-Rutz et al., 2004]. These data let us to hypothesize that Val/Val genotype also interacts with restricted fetal growth to increase anger-related traits in suicide attempters. The fact that in our study male suicide attempters do not display a significant difference in anger-related traits according to the COMT genotype could be due to the smaller sample size, but it could also indicate that various personality patterns contribute differently to the risk of suicidal behavior. Engstrom et al.  categorized suicide attempters by cluster analysis into different groups according to temperamental traits. One of the identified clusters was characterized by ‘‘neurotic, impulsive and aggressive’’ traits and was mainly seen in borderline and histrionic patients. Characteristics of high levels of anger and impulsivity could be more frequent in female suicide attempters, which represent an elevated proportion (70.7%) of our clinical sample. As anger and impulsivity seem to be tightly related in increasing the risk of selfdestructive or self-harming behaviors [Milligan and Waller, 2001; Mann, 2003], future investigations should analyze the effects of COMT genotype or other candidate genes on a phenotype combining the characteristics of both anger- and impulsivity-related personality traits. Finally, anger-related personality traits could be phenotypically related to various cognitive processes, such as attentional control tasks, executive functioning or higher order mental processing, all of which have recently been shown to be negatively affected by the Val allele [Blasi et al., 2005; Bruder et al., 2005; de Frias et al., 2005]. 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