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Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton (FL): CRC Press/Taylor & Francis; 2012.

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The Neurobiological Basis of Suicide.

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Chapter 18Intermediate Phenotypes in Suicidal Behavior Focus on Personality

and .

18.1. RISK FACTORS OF SUICIDAL BEHAVIOR

Every year over 1 million people commit and over 10 million people attempt suicide. This is one suicide every 40s and one suicide attempt every 3s worldwide. Suicide accounts for almost 2% of the world’s death and it has emerged as one of the leading causes of death among individuals aged 15–34 years in most of the countries (Bertolote, 2001; Cantor, 2000; WHO, 2011). Attempted suicide is currently regarded as the most important predictor of a future death from suicide (Gunnell and Lewis, 2005). Almost one-quarter of suicides are preceded by nonfatal suicidal behaviors in the previous year (Owens and House, 1994) and ~2% of suicide attempters end their own life during the 12 months subsequent to the index event (Owens et al., 2002). In the years following an initial suicide attempt, studies indicate a suicide risk ranging from 3.2% (Suokas and Lonnqvist, 1991) to 11.6% (Nielsen et al., 1995) within 5 years, 4.8% (Beck and Steer, 1989) to 12.1% (Nielsen et al., 1995) within 10 years, 6.7% within 18 years (De Moore and Robertson, 1996), and 10%–15% within lifetime (Suominen et al., 2004).

Suicidal behavior is complex and frequently classified by differentiating between suicidal ideation, suicide attempts, and completed suicide. It is not attributable only to one single cause but is a consequence of complex interactions of several risk factors like, for example, medical (e.g., mental disorders and chronic pain), psychological (e.g., hopelessness and aggressiveness), psychosocial (e.g., social isolation), social (e.g., lack of social support), cultural (e.g., religion), socioeconomic (e.g., unemployment), and biological (e.g. genetics and disorders in brain functioning).

Early work especially focusing on demographic, psychiatric, and psychological factors found, among others, that being younger, unmarried, unemployed, having a psychiatric illness, feeling hopeless, and having recently experienced a stressful life event were directly correlated with an increased risk of suicide and suicidal behaviors, whereas religiousness, spirituality, and social support were found to have a protective effect. Furthermore, it was reported that being female was associated with a higher risk of suicidal attempt whereas being male was related to a greater risk of death associated to suicide (Nock et al., 2008). Beside all other risk factors, especially personality seems to have a high impact on suicidal behavior (Brezo et al., 2006).

18.2. PERSONALITY AND SUICIDAL BEHAVIOR

18.2.1. Aggression

Aggression has been associated with suicidal behavior at least since the early findings by Asberg et al. (1976). Since then a high amount of studies could replicate this link (Corbitt et al., 1996; Malone et al., 1995; Oquendo et al., 2000, 2006).

Furthermore, aggression has been related to suicidality in mood disorders. Straub et al. (1992) compared four groups of depressed women with suicide ideation, violent suicide attempt, nonviolent suicide attempt, and depression without suicidality. Aggression scores, together with other psychophysiological features, were shown to differentiate between these groups. In their sample of psychiatric inpatients (51% with mood disorder), Mann et al. (1999) found higher rates of lifetime aggression in suicide attempters compared to non-suicidal patients. Oquendo et al. (2000) and Grunebaum et al. (2006) reported that lifetime aggression traits did correlate with suicide attempts in patients with mood disorder. In a recent study, regression tree analysis applied to a large group of bipolar patients identifying current depression and aggressive traits as indicators of a remote suicide attempt (Mann et al., 2008). A link between aggression and suicidal behavior has also been shown in schizophrenia (Hong et al., 2004; Malone et al., 2003; Mann et al., 2008; McGirr and Turecki, 2008), borderline personality disorder (Brodsky et al., 2006; Horesh et al., 2003), substance use disorders (Sher et al., 2005, 2008; Tremeau et al., 2008), and nonclinical samples (Ille et al., 2001).

18.2.2. Impulsivity

Furthermore, aggressive behaviors have been shown to correlate with impulsivity (Oquendo et al., 2000, 2004; Zouk et al., 2006), suggesting that an impulsive– aggressive dimension may predispose to suicidality (McGirr and Turecki, 2007; Turecki, 2005).

A variety of studies, in particular conducted by the McGill Group for Suicide Studies (Canada), demonstrated an association between impulsive personality traits and lifetime aggression in suicidal subjects (McGirr and Turecki, 2007, 2008; Turecki, 2005; Zouk et al., 2006). Such findings have led researchers to speculate on a common impulsive–aggressive dimension that may predispose to suicidality (McGirr and Turecki, 2007; Turecki, 2005). Conversely, others reported a weak correlation between measures of aggression and impulsivity (Critchfield et al., 2004). Such inconsistent findings may be due to different operationalizing criteria and instruments used to assess aggression and impulsivity in suicide research. Aggression has been measured by self-report questionnaires on aggressive tendencies (Doihara et al., 2008; Giegling et al., 2006, 2007; Pompili et al., 2008) or operationalized as a lifetime history of aggressive behaviors (McGirr and Turecki, 2008; Oquendo et al., 2004, 2007; Renaud et al., 2008; Zouk et al., 2006). Impulsivity may be conceptualized as the inability to resist impulses, which, from the strict phenomenological point of view, refers to explosive and instantaneous, automatic, or semiautomatic psychomotor actions that are characterized by their sudden and incoercible nature (Kempf, 1976). A more behavioral definition considers impulsivity as a predisposition toward rapid, unplanned reactions to internal or external stimuli without regard to the negative consequences of these reactions to the impulsive individual (Moeller et al., 2001). The lack of consensus about a definition of impulsivity leads to difficulties in its measurement. Impulsivity self-report scales exhibit low intercorrelations, are subject to response bias, and incorporate multiple subfactors (Gorlyn, 2005). In clinical evaluation of suicide attempt, premeditation is a critical factor. Indeed, different interventions may be necessary for the subjects who have carefully planned their attempt for a long period or are liable to act out suddenly in response to circumstances. A considerable proportion of attempts are made without premeditation. Although such impulsive suicide attempts are often pointed to being different from planned attempts, few studies have compared the two forms yielding inconsistent results (Brown et al., 1991; Mitrev, 1996; Polewka et al., 2005; Simon et al., 2001; Witte et al., 2008; Wyder and De Leo, 2007). Methods chosen for suicide attempt should be carefully considered in prevention tasks as they vary considerably in terms of violence and lethality. Research suggests that personality traits of anger, aggression, and impulsivity may influence the choice of suicide methods, although there are no consistent results from available studies (Dumais et al., 2005; Held et al., 1998; Seidlitz et al., 2001; Straub et al., 1992).

18.2.3. Anger

Anger has also been indicated as a risk factor for suicidality. Trait anger has been associated with a previous history of attempted suicide in a sample of adolescent inpatients with a variety of psychiatric disorders (Goldston et al., 1996). In adolescent suicide attempters, high levels of anger expression predicted self-mutilative behavior and a self-reported wish to die. In older suicide attempters, higher anger/hostility correlated with a greater number of attempts, while lower levels of anger predicted higher intent to die and higher lethality of methods (Seidlitz et al., 2001). Furthermore, the association between anger and suicidality has been demonstrated in depression (Painuly et al., 2007; Seidlitz et al., 2001; Velting et al., 2000), eating disorders (Nickel et al., 2006; Verkes et al., 1996; Youssef et al., 2004), and alcohol use disorders (Haw et al., 2001). In adolescent samples, studies reveal a strong correlation of anger with self-harm (Hawton et al., 1999) and attempted suicide (Cautin et al., 2001; Esposito et al., 2003; Kirkcaldy et al., 2006; Stein et al., 1998).

18.2.4. Temperament

Temperament and character evaluation has revealed significant differences between individuals with and without suicide attempts. Though there is a relatively wide agreement on the basic definition of temperament (Cloninger et al., 1994; Rettew and McKee, 2005; Thomas and Chess, 1977), a number of different measurement instruments have been used that differ in temperament definitions. However, a large overlap exists among at least three of them: Temperament and Character Inventory (TCI) (Cloninger et al., 1994), NEO Personality Inventory (NEO-PI) (Costa and McCrae, 1992), and Eysenck Personality Questionnaire (EPQ) (Eysenck and Eysenck, 1964, 1975). TCI harm avoidance (HA) and novelty seeking (NS) are, respectively, correlated with neuroticism (N) and extraversion (E) as defined by NEO-PI and EPQ (Costa and McCrae, 1995; De Fruyt et al., 2000).

Available literature has analyzed heterogeneous groups of suicide attempters: patients with mood disorders (Engstrom et al., 2004; Sayin et al., 2007) and eating disorders (Anderson et al., 2002; Bulik et al., 1999; Favaro et al., 2008), substance-dependent patients (Evren and Evren, 2005, 2006), and unselected psychiatric patients (Becerra et al., 2005; Calati et al., 2008; Guillem et al., 2002). Overall these studies report elevation in the temperament dimensions of NS and HA (Becerra et al., 2005; Calati et al., 2008) and decrease in the character dimensions of self-directedness (SD) and cooperativeness (CO) (Becerra et al., 2005; Calati et al., 2008; Evren and Evren, 2006; Favaro et al., 2008) in suicide attempters compared to non-suicidal controls. In addition, a part of the studies indicate temperament and character differences between attempted suicide and self-injurious behaviors (Evren and Evren, 2005; Favaro et al., 2008). Personality traits have been used to identify groups of suicidal individuals such as repeated attempters (Evren and Evren, 1996; Laget et al., 2006), older attempters (Duberstein et al., 2000), and completers (Useda et al., 2007). Overall, these studies report elevation in the temperament dimensions of “NS” and “HA” (Becerra et al., 2005; Calati et al., 2008) and decrease in the character dimensions of “SD” and “CO” (Becerra et al., 2005; Evren and Evren, 2006; Favaro et al., 2008) in suicide attempters compared to non-suicidal controls. Giegling et al. (2009c) showed that higher aggression scores were predicted by being male, meeting criteria for borderline personality disorder, and having higher angry temperament scores as assessed by STAXI. Furthermore, temperament dimensions associated with self-aggression were high harm avoidance, high impulsivity, and low self-directedness; state anger, inwardly directed anger, and inhibition of aggression were also predictors of self-aggression. Additionally, impulsivity and harm avoidance have emerged as temperament dimensions independently associated with self-aggressive tendencies in personality.

18.2.5. Neuroticism

Neuroticism, a personality trait, reflects a tendency toward negative mood states and has been included in most theories of personality since its introduction. Studies have consistently demonstrated associations between an individual’s level of neuroticism and likelihood of having symptoms or syndromes of suicidal behavior, depression, or anxiety (Brandes and Bienvenu, 2006; Widiger and Trull, 1992). Data from a number of studies, including two large, population-based, longitudinal samples (Kendler et al., 1993; Ormel et al., 2004), indicate that neuroticism acts as a premorbid vulnerability trait for major depression. Furthermore, several studies support the hypothesis that neuroticism mediates some of the elevated comorbidity between depressive and anxiety disorders as well as suicidal behavior (Khan et al., 2005).

18.2.6. Personality: An Intermediate Phenotype of Suicidal Behavior?

The identification of personality features related to suicide attempts may be useful to prevent suicide mortality, due to the strong correlation between attempted and complete suicide.

Intermediate phenotypes emerged recently to the most valuable tool in the search for the genetic underprinting of complex traits and diseases. Clinically defined diseases (e.g., stroke) or behaviors (e.g., suicide) can be regarded as the sum of many risk factors, which can be decomposed into intermediate phenotypes (e.g., lipid levels in the case of stroke and trait anger levels in the case of suicide). Genetic factors contributing to intermediate phenotypes will generally be easier to identify because of the improved signal-to-noise ratio in the fraction of variance explained by any single factor. Studies using a single clinical end point (e.g., stroke) have one chance of success, whereas studies that also collect intermediate phenotypes are more likely to help understand the contribution of genetic factors to characteristic components of disease or behavior. Especially suicide-related behavior may represent a heterogeneous trait implying that the current clinically defined phenotype might not be optimal for genetic studies. Therefore, simpler, quantifiable measures of functioning may be more useful in gene discovery. This approach helps to circumvent questions about etiological models.

Intermediates can be regarded as syntheses of subsets of proximal risk factors, both environmental and genetic. The rationale for the use of intermediate phenotypes in gene discovery is that the intermediate phenotypes associated with, for example, a behavioral trait are more elementary compared to clinical phenotypes. This also implies that the number of genes required to produce variations in these traits may be fewer than those involved in producing a diagnostic entity. Intermediate phenotypes are thus likely to bridge the gap between genes and clinical phenotypes.

Some intermediate phenotypes used in psychiatry are state independent, are associated with the illness, and co-segregate in families with the disease. In summary, intermediate phenotypes have emerged as an intriguing concept in the study of complex neuropsychiatric traits. Intermediate phenotypes represent simpler phenotypes than psychiatric diagnoses, which can result in more straightforward and successful genetic analysis (Gottesman and Gould, 2003).

Moreover personality traits, which are partly under genetic control, may be intermediate phenotypes for the genetic component of suicidal behavior (Baud, 2005).

18.3. GENETIC COMPONENT OF SUICIDAL BEHAVIOR IN RELATION TO PERSONALITY

Risk of suicide-related behavior is supposed to be determined by a complex interplay of sociocultural factors, traumatic life experiences, psychiatric history, personality traits, and genetic vulnerability. The latter is supported by adoption and family studies, indicating that suicidal acts have a genetic contribution that is independent of the heritability of Axis I and II psychopathology (Brent and Mann, 2005; Roy and Linnoila, 1986; Roy et al., 1991; Schulsinger et al., 1979). The heritability for serious suicide attempts was estimated to be 55% (Statham et al., 1998), and genetic association studies are valuable bottom-up tools to reveal underlying neurobiological pathways of this complex trait. Most genetic association studies in this context focused on genes that are involved in serotonergic neurotransmission. Serotonergic function was regarded to be crucial for the regulation of impulsive and aggressive behavior, which in turn has been demonstrated to correlate with suicidal behavior in various studies (Mann, 2003).

18.3.1. Serotonergic System

Many biological studies investigating the postmortem brains of suicide victims have shown alterations of the serotonergic system, especially in the prefrontal cortex (for review, see Arango et al., 1997). Furthermore, clinical studies found a relationship between lower levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) and suicidal behavior (Asberg, 1997). Low cerebrospinal fluid (CSF) concentrations of the serotonin metabolite 5-HIAA are regarded as a putative indicator for low serotonin turnover (Asberg, 1997; Asberg et al., 1976, 1987). It is a relatively enduring trait that is partially genetically controlled as suggested by studies in humans (Oxenstierna et al., 1986), and demonstrated in rhesus monkeys (Higley et al., 1992; Westergaard et al., 1999). In these animals, low CSF 5-HIAA is associated with aggressiveness, low social affiliation, high-risk behavior, and premature mortality (Higley et al., 1996a,b; Mehlman et al., 1994). In humans, 5-HIAA in the CSF correlates inversely with various aggressive behaviors as demonstrated in healthy and psychiatric samples throughout the life span. Although there are some negative reports, taken together, the vast majority of findings suggest that lowered 5-HIAA is related to the vulnerability for aggressive behavior (Asberg, 1997; Asberg et al., 1987; Lee and Coccaro, 2001), and there seems to be a relationship between lower serotonergic function and aggressive, impulsive, and suicidal behavior. Therefore, genetic studies investigated the serotonergic system in suicidal behavior and personality traits from the very beginning.

18.3.1.1. Tryptophan Hydroxylases 1 and 2

The enzyme tryptophan hydroxylase (TPH) is involved in the biosynthesis of serotonin, converting l-tryptophan in a rate-limiting step into 5-hydroxytryptophan. An early meta-analysis (Lalovic and Turecki, 2002) did not find an association of the commonly studied intron 7 A218C (TPH1) single nucleotide polymorphism (SNP) with suicidal behavior per se. A further meta-analysis summarized the results of seven studies investigating the A218C SNP in Caucasians (Rujescu et al., 2003b) and found a higher frequency of the A218 allele in the patients with suicidal behavior, strongly suggesting that this TPH1 polymorphism is associated with suicidal behavior in Caucasians. A further meta-analysis included nine studies and confirmed the association between the A218C polymorphism and suicidal behavior using both the fixed effect method and the random effect method (Bellivier et al., 2004), and in 2006 Li and He provided a meta-analysis on 22 studies and showed further support for association (Li and He, 2006).

Interestingly, this risk allele “A” was also associated with higher measures of aggression and a tendency to experience unprovoked anger and an expression of anger more outwardly (Manuck et al., 1999). This result was further supported by Rujescu et al. (2002) who showed that A-carrier had higher scores on the Trait Anger Scale of the State Trait Anger Expression Inventory (STAXI) and especially on the subscale “Angry Temperament” in two independent samples (healthy controls and suicide attempters). An involvement of TPH1 in anger and aggression phenotypes could furthermore recently been presented by Baud et al. (2009) who showed that suicide attempters carrying the AA genotype scored significantly lower on the Anger Control subscale than C-allele carrier, which confirms the hypothesis that the TPH1 gene could confer a vulnerability to suicidal behavior through a reduced capacity to control anger, which in turn may represent a common psychopathological and behavioral pathway to suicidal behavior in an important subgroup of clinical subjects.

Walther et al. (2003) discovered a second TPH isoform in mice, termed TPH2, that seems to control the brain serotonin synthesis (Zhang et al., 2004). Breidenthal et al. (2004) screened the coding and exon-flanking intronic sequence of the TPH2 gene and identified several genetic variants that might serve as markers for association studies. The investigation of 10 SNPs in the TPH2 gene in a sample of 263 suicide victims and 266 ethnically matched healthy controls showed an association of one SNP with completed suicide (Zill et al., 2004). Since then several case-control studies were provided showing positive and negative results (for review, see Tsai et al., 2011). Interestingly, polymorphisms in the TPH2 gene were also associated with personality traits like aggression or impulsivity, for example, Kulikov et al. (2005a,b) reported that the C1473G polymorphism in the TPH2 gene is associated with intermale aggression in mice (see also Osipova et al., 2009, 2010).

18.3.1.2. Monoamine Oxidase A

The gene coding for the monoamine oxidase A (MAOA) contains a variable number of tandem repeats (VNTR) polymorphism in the promoter region. The 30 bp repeated sequence is present in 3, 3.5, 4, or 5 copies, and alleles with 3.5 or 4 copies are transcribed 2–10 times more efficiently than those with 3 or 5 copies (Sabol et al., 1998). MAOA is one of the key enzymes in the metabolism of serotonin as well as noradrenalin. Studies investigating the possible association of this MAOA-uVNTR polymorphism and suicidal behavior yielded inconsistent results. Several groups found no significant differences in genotype or allele distribution between subjects with suicidal behavior and comparison groups (Huang et al., 2004b; Kunugi et al., 1999; Ono et al., 2002), whereas one investigation delivered a significant association (Ho et al., 2000). Ho et al. examined this VNTR and the Fnu4H1 polymorphism in a sample of patients suffering from bipolar affective disorder. They found the VNTR variant to be associated with a history of suicide attempts, especially in females. The Fnu4H1 RFLP only showed significant differences in allele frequencies for female subjects, but not in the total sample. Another study showed a strong association of the high activity-related EcoRV allele and depressed suicide in male subjects, but not in females or the total sample (Du et al., 2002).

Additionally, the MAOA gene seems to be implicated in the control of aggressive or impulsive behavior. Brunner et al. (1993a,b) reported a large Dutch family with a new form of X-linked mild mental retardation, with all affected males showing aggressive, impulsive, and sometimes violent behavior and one case of attempted suicide. A second investigation showed that each of five affected males had a point mutation in the MAOA gene, which changes a glutamine to a termination codon (Brunner et al., 1993a,b). Interestingly, a recent study by Zalsman et al. (2011) could report an association with low activity MAOA genotypes and clinical traits of impulsive aggression and suicidality in adolescents.

18.3.1.3. Serotonin Transporter

The serotonin transporter (5-HTT) is located on the presynaptic membrane of serotonergic neurons and is responsible for the reuptake of released serotonin from the synaptic cleft. The 5.-promotor region of the 5-HTT gene contains a functional insertion/deletion variant (5-HTTLPR) with former two and latter three common alleles that were designated as “short” (s) and “long” (lA and lG). The 5-HTT transcription and serotonin reuptake are higher in cells containing the homozygous ll genotype, compared with cells having the ls or ss forms (Lesch et al., 1996).

A meta-analysis conducted by Anguelova et al. (2003) included 12 studies investigating the 5-HTT promoter polymorphism. The study samples compromised 10 Caucasian populations, one U.S. population (80% Caucasians, 20% others) and one Chinese sample. They pooled a total number of 1168 cases (suicide completers and suicide attempters) and 1371 controls and found a significant association of the s-allele with suicidal behavior as a whole. They furthermore observed an overall association if only studies that investigated suicide attempters and control subjects were considered, but no association was found by comparing only suicide completers versus controls.

A second meta-analysis, including 18 studies with 1521 suicide attempters or completers and 2429 controls, delivered different results (Lin and Tsai, 2004). In contrast to the investigation of Anguelova et al. (2003), Lin and Tsai (2004) found no overall association of 5-HTTLPR alleles with suicidal behavior. This was also true if only the 15 studies with subjects of Caucasian origin were examined. The authors also compared the allelic and genotype distribution between 190 violent suicide attempters or completers and 733 normal control subjects. They observed a significant association of the s-allele with violent suicidal behavior, which is mainly characterized by the use of highly lethal and violent methods like hanging or shooting, but not with nonviolent suicide. Lin and Tsai (2004) concluded that violent suicidal subjects might be a relatively homogeneous group and that patients carrying the s-allele are likely to act more impulsive and aggressive. Additionally, the genotypes containing the s-allele were more frequent in suicide attempters than in nonattempters with the same psychiatric diagnoses. Li and He (2007) reviewed 39 studies that examined the association between functional polymorphism of 5-HTTLPR and suicide attempts in groups with psychiatric diagnoses. Their report suggested a significant association with the s-allele. In conclusion, there is evidence that the 5-HTTLPR polymorphism is involved in the predisposition to suicidal behavior. More detailed studies are required, as it seems that this functional variant is associated with particular intermediate phenotypes of suicidal behavior (for review, see Canli and Lesch, 2007; Lesch, 2007; Murphy and Lesch, 2008).

18.3.1.4. 5-HT1A Receptor

Lemonde et al. (2003) examined the common C-1019G SNP in the promoter region of the 5-HT1A gene in a sample of 102 suicide victims and 116 healthy controls, all of French-Canadian origin. They found the G-allele to be significantly overrepresented in the suicide group, and the homozygous G/G genotype was four times more frequent among suicide completers. This association could not be replicated by Huang et al. (2004a). The investigation of the structural polymorphisms Pro16Leu and Gly272Asp revealed no association with suicidal behavior in Japanese subjects (Nishiguchi et al., 2002), and the result for the Pro16Leu SNP was replicated by a second Japanese group (Ohtani et al., 2004). But so far no positive association could be found for anger- or aggression-related phenotypes and genetic variants in this gene (Serretti et al., 2007a,b, 2009).

18.3.1.5. 5-HT1B Receptor

Suicidality and impulsive aggression are partially heritable, and postmortem brain studies suggest that abnormalities in serotonin 1B may be associated with suicide. Studies of serotonin 1B “knockout” mice show an increase in aggressive behavior relative to wild-type mice (Saudou et al., 1994). Interestingly, Jensen et al. (2009) could show that a common polymorphism in serotonin receptor 1B mRNA moderates regulation by miR-96 and associates with aggressive human behaviors. Furthermore, Conner et al. (2010) show that functional polymorphisms in the serotonin 1B receptor gene (HTR1B) predict self-reported anger and hostility among young men. Whereas there seems some support for the involvement of the HTR1B gene in aggression, no association could be found with suicidal behavior per se so far (Arango et al., 2003; Hong et al., 2004; Huang et al., 1999, 2003; New et al., 2001; Nishiguchi et al., 2001; Pooley et al., 2003; Rujescu et al., 2003c; Stefulj et al., 2004; Tsai et al., 2004b; Turecki et al., 2003), and also a recent meta-analysis showed no significance (Kia-Keating et al., 2007).

18.3.1.6. 5-HT2A Receptor

The increased density of brain and platelet serotonin 2A (5-HT2A) receptors in subjects with suicidal behavior is evidenced by several studies (Bachus et al., 1997). Thus, the 5-HT2A receptor gene has been regarded as a major candidate for the genetic susceptibility to this behavior (Mann, 1998). However, a metaanalysis pooling nine studies with altogether 596 suicide completers or attempters and 1003 healthy controls could not find any association with the T102C SNP (Anguelova et al., 2003). A later meta-analysis of 25 studies could furthermore not find any association with this SNP but interestingly, the meta-analysis of a promoter SNP in this gene (A-1438G; rs20070040) could show association with suicidal behavior (Li et al., 2006). To test for intermediate phenotypes, Giegling et al. (2006) investigated the association of the three SNPs in the 5-HT2A gene with anger-and aggression-related personality traits. CC homozygotes for the functional SNP rs6311 reported more anger-related traits in general and had higher scores on the subscales “Trait Anger” with its “Angry Reaction” component and lower scores on the subscale “Anger Out.” Accordingly, the C-allele of the functional SNP was also associated with aggression-related traits and more specifically with less aggression inhibition. The SNPs predominantly analyzed in association with personality traits to date were rs6311 and rs6313. These SNPs are in strong linkage disequilibrium (LD) being in the promoter and at the beginning of the gene, respectively. A large quantity of studies was published. In particular, platelet serotonin 2A receptor sites have been found associated with impulsivity and aggression in a positron emission tomography (PET) study (Coccaro et al., 1997). Moreover, rs6311 was found to be associated with impulsive traits in alcohol dependents, measured with the Baratt Impulsiveness Scale (BIS) (Preuss et al., 2000). This was the first report on an association of a 5-HT2A promoter SNP with personality dimensions, which is partially confirmed by more recent reports on the same variant (Ni et al., 2006; Nomura, 2006). Subsequently, 5-HT2A SNPs have been found to be associated with low anxiety-related traits, which are negatively related to impulsive traits (Golimbet et al., 2004; Rybakowski et al., 2006). In addition, TCI self-transcendence was related to the rs6311 SNP (Ham et al., 2004). On the other hand, a considerable number of negative results have also been reported regarding the involvement of 5-HT2A in personality traits (Berggard et al., 2003; Blairy et al., 2000; Jonsson et al., 2001; Kusumi et al., 2002; Lochner et al., 2007; Tochigi et al., 2005). Serretti et al. (2007a,b) investigated a few SNPs with personality traits as measured with the TCI in three independent samples including healthy subjects and patients. Although the SNP rs594242 showed an association with SD (p = 0.003) in the German sample, and rs6313 was marginally associated with NS (p = 0.01) in the Italian sample, this study does not support a major effect of these SNPs on temperament so far.

18.3.2. Dopaminergic System and Catecholamines

CSF studies provided support for an involvement of the dopaminergic system in suicidal behavior showing correlations between low levels of the dopamine metabolite homovanillic acid and suicidal behavior (Ryding et al., 2008).

18.3.2.1. Dopamine Receptors

The first study investigated a SNP in the 3.-UTR of exon 8 in the dopamine D2 receptor gene and showed that the A/A genotype was associated with an increased number of suicide attempts (Finckh et al., 1997). Furthermore, the functionally relevant -141C insertion/deletion polymorphism was investigated by Ho et al. (2000) who found no differences in allele frequencies in subgroups of unipolar and bipolar patients with or without suicidal behavior. Johann et al. (2005) showed an association for this variant to suicidality in patients with alcohol dependence, although this association did not remain significant after Bonferroni correction, and Suda et al. (2009) reported an association of the -141C Ins/Del and TaqIA polymorphisms with suicide attempters. Two studies examined the association of a 48bp repeat polymorphism in the dopamine receptor D4 gene with suicide attempts. Both groups did not find any evidence of an implication of this polymorphism in suicidal behavior (Persson et al., 1999; Zalsman et al., 2004).

The first study on genetic variants in the dopamine receptor genes by Sweet et al. (1998) showed no association with the DRD2 S311C polymorphism nor the presence of long alleles for the DRD4 exon III repeat sequence and also not with the DRD3 gene, while there was a weak association with one SNP in the DRD1 gene an aggression. Furthermore, Chen et al. (2005) provided evidence for a positive correlation of both the dopamine D2 receptor gene (DRD2) and the dopamine transporter gene (DAT1) polymorphisms with pathological violence in adolescents. As the efficacy of dopamine D2 receptor (DRD2) blocking antipsychotic drugs in borderline personality disorder treatment also suggests involvement of the dopamine system in the neurobiology of that disease, Nemoda et al. (2010) tested the dopamine dysfunction hypothesis of impulsive self- and other damaging behaviors. The DRD2 TaqI B1-allele and A1-allele were associated with borderline traits, also, the DRD4 -616 CC genotype appeared as a risk factor, but only the DRD4 promoter finding was replicated in the independent sample of psychiatric inpatients. No association was found with the COMT and DAT1 polymorphisms. Further support for the involvement of genetic polymorphisms in aggression and impulsivity comes from Retz et al. (2003) whose results suggest that variations of the DRD3 gene are likely involved in the regulation of impulsivity and some psychopathological aspects of ADHD related to violent behavior. There are many other studies on this matter (for review, see Craig and Halton 2009).

18.3.2.2. Dopa Decarboxylase

Components of the dopaminergic system have been previously associated to suicidal behaviors (Oquendo and Mann, 2000; Rujescu et al., 2003a; Ryding et al., 2008) and aggression regulation (Pitchot et al., 1992, 2001; Rujescu et al., 2003a), hence making the pathway a good candidate to be studied in this condition. Dopamine is synthesized from the amino acid tyrosine undergoing two steps: the first producing DOPA by tyrosine hydroxylase (TH) and the second from DOPA to dopamine by the DOPA decarboxylase (DDC). Both steps could therefore modulate the system. Low concentrations of homovanillic acid, a metabolite produced by the catabolism of dopamine, have been found in CSF of depressed patients who attempted suicide compared to controls (Engstrom et al., 1999), supporting the hypothesis of a diminished dopaminergic neurotransmission in suicidal behavior (Roy et al., 1992), though not unequivocally (Asberg, 1997). DDC is located on chromosome 7p12.3-p12.1, and consists of 15 exons spanning >85 kb (Sumi-Ichinose et al., 1992). DDC gene variants have been investigated in relation to suicide-related behavior or phenotypes by Giegling et al. (2008a, 2009b) who showed some marginal associations with suicide, violence, anger, aggression, and temperament but no major effect was seen for this gene.

18.3.2.3. Tyrosine Hydroxylase

The TH is the rate-limiting enzyme in the biosynthesis of noradrenalin, and different studies reported alterations of TH levels in the locus coeruleus of suicide victims (Pandey and Dwivedi, 2007). A Swedish study (Persson et al., 1999) examined a penta-allelic short tandem repeat in the first intron of the TH gene. The sample consisted of 118 adult suicide attempters and 78 control subjects. This study reported a tendency for a low incidence of the TH-K1 allele among all suicide attempters compared to the controls. Furthermore, a significant association between the TH-K3 allele in a subgroup of patients with adjustment disorders and attempted suicide was found (Persson et al., 1999). Giegling et al. (2008a, 2009b) investigated SNPs in the TH gene in 571 suicide attempters and controls and found only marginal associations with suicidal behavior, which did not hold after correction for multiple testing (rs3842727 uncorrected p = 0.023). As other SNPs showed no association, this study does not support a major involvement of TH gene variants in suicidal behavior and related traits. Interestingly, De Luca et al. (2008) found a trend for a TH polymorphism and a higher severity of suicidal behavior (p = 0.060) but the power was too low and further studies are needed to make any conclusions regarding the involvement of TH SNPs in suicidal behavior. Furthermore, Giegling et al. (2009b) presented interaction effects of genotype and diagnosis with TH SNPs and temperament having a greater effect on the respective personality dimensions in the group of suicide attempters.

18.3.2.4. Catechol-O-Methyltransferase

The catechol-O-methyltransferase (COMT) is a major enzyme involved in the inactivation of the catecholamines, dopamine and noradrenalin. One functional polymorphism in the COMT gene, in which valine (Val) at codon 158 is replaced with methionine (Met), was studied intensively in psychiatric diseases as well as in suicidal behavior and related traits including aggression.

Lachman et al. (1996) showed that this polymorphism is due to a G-to-A transition at codon 158 of the COMT gene, resulting in a valine-to-methionine substitution. This SNP causes differences in the functional ability of the enzyme to catabolize dopamine (Lachman et al., 1996).

Several studies investigated the association of COMT SNPs with a wide range of phenotypes such as psychiatric disorders and personality traits. COMT has been hypothesized as a risk factor, for example, for schizophrenia (Williams et al., 2007), attention deficit hyperactivity disorder (Kebir et al., 2009), alcoholism (Serý et al., 2006), bipolar disorder, and others (Dickinson and ElvevÅg, 2009).

For suicidal behavior, Kia-Keating et al. (2007) provided a meta-analysis based on six related studies including 519 cases and 933 control subjects. There was evidence of a significant association between the COMT 158Met polymorphism and the suicidal behavior (odds ratio [OR] = 1.25, 95% confidence interval [CI] = 1.01–1.56, z = 2.03, p = 0.04). Although the results for COMT were not influenced by publication bias, the significance of the combined results was related to the gender of the case and control subjects. The results for COMT support past studies that have found a relationship between suicidal behavior and COMT, and have also found that the relationship differs for males and females. They speculate that due to a higher number of suicide attempts among females and a higher number of committed suicides among males, it could be possible that COMT is related to the lethality of suicide attempts.

The latest meta-analysis on COMT and suicidal behavior was provided by Calati et al. (2011) who included 10 studies with 1324 patients and could not find an association.

Interestingly, Rujescu et al. (2003a) found that Val-carriers expressed their anger more outwardly, whereas Met-carriers expressed it more inwardly and reported more state anger, as assessed by the self-report questionnaire STAXI. Furthermore, COMT was found related to HA and neuroticism (Eley et al., 2003; Enoch et al., 2003; Stein et al., 2005), NS and extraversion (Reuter and Henning, 2005; Tsai et al., 2004a), and anger-related traits connected with violent suicide (Rujescu et al., 2003a). A detailed summary on 46 studies of the association of COMT and personality traits can be found in Calati et al. (2011).

18.3.3. Outlook

There is evidence for the involvement of genetic variants in other than serotonergic and dopaminergic genes in suicidal behavior and related phenotypes. Further studies will show to which proportion they will play a role and which findings will be replicated in the future. There are also several studies on aggression or impulsivity coming directly from animal studies showing some evidence for involvement (e.g., NCAM1, neuronal cell adhesion molecule gene, Giegling et al., 2010; estrogen receptor genes, Giegling et al., 2008b, 2009a; NOS-I and NOS-III genes, Rujescu et al., 2008; tachykinin receptor 1 gene, Giegling et al., 2007; ABCG1, Giegling et al., 2006; Gietl et al., 2007; Rujescu et al., 2000; and many more, Rujescu et al., 2007).

Beside candidate gene approaches, new hypothesis-free approaches arised due to the new technical possibilities in genotyping. Recent progress in the field of parallel SNPs typing of up to 1 million variants at once has provided proof of principle and yielded several genes showing a strong association with complex diseases. For example, van den Oord et al. (2008) published a genome-wide study on neuroticism as an intermediate phenotype of suicidal behavior. More than 420,000 genetic markers were tested for their association with neuroticism in a genome-wide association study (GWAS). The GWAS sample consisted of 1227 healthy individuals ascertained from a U.S. national sampling frame and available from the National Institute of Mental Health genetics repository. The most promising markers were subsequently tested in a German replication sample comprising 1880 healthy individuals. The most promising results were SNPs in the gene MAMDC1, which is proposed to be involved in regulating neuronal migration and axonal guidance. Further genome-wide studies on personality were provided by Terracciano et al. (2010) and Calboli et al. (2010). The future will show if these results can be replicated.

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© 2012 by Taylor & Francis Group, LLC.
Bookshelf ID: NBK107202PMID: 23035288
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