Association of aggressive behavior in Korean male schizophrenic patients with polymorphisms in the serotonin transporter promoter and catecholamine-O-methyltransferase genes
Introduction
The incidence of aggressive behavior in schizophrenia has been reported to be much higher than that in the general population (Swanson et al., 1990). Steinert et al. (1999) reported that aggressive and violent behavior against the self and others frequently occurs in schizophrenia during the first 2 years of illness, and that such behavior constitutes one of the major causes of rehospitalization. The causes of aggressive behavior are various, and the role of the neurotransmitters believed to be involved in the mediation of this behavior is undoubtedly complex.
Accumulating evidence suggests that genetic factors partially determine aggressive, antisocial, and criminal behavior Cadoret et al., 1995, Brennan et al., 1996, Cairns, 1996, Tecott and Barondes, 1996, Miles and Carey, 1997. Among the particular gene polymorphisms that have been posited to be involved in aggressive behavior, the catechol-O-methyl-transferase (COMT) gene and the serotonin transporter promoter region (5-HTTPR) have been the focus of recent research attention.
Strous et al. (1997) and Lachman et al. (1998) reported a correlation between aggressive behavior in schizophrenia and the low-activity allele of the COMT gene (COMTL). The COMT gene inactivates dopamine. Enzymatic activities also are reduced by a common polymorphism at this gene. Such reduction is due to a G-to-A transition at codon 158, which results in the valine (high activity allele, COMTH) to methionine (low activity allele, COMTL) substitution forming a three- to four-fold reduction of variants in enzymatic activities (Lachman et al., 1996).
Kotler et al. (1999a) suggested in their study of a correlation between the COMT gene polymorphism and aggressive behavior that the involvement of COMT in violent behavior underlines the importance of nonserotonergic mechanisms in such conduct since serotonin is not a substrate for this enzyme. However, serotonin has frequently been suggested as a causative factor for impulsive, violent, and dangerous behavior in humans and animals Hilakivi-Clarke and Goldberg, 1993, Cases et al., 1995, Kunz et al., 1995.
Since the mid-1970s, many studies have shown that impulsive-aggression and suicidal behavior are correlated with serotonin transmission (Åsberg et al., 1976). The magnitude and duration of serotonin transmission are mainly associated with the serotonin transporter (5-HTT), which regulates the uptake of serotonin at synaptic junctions Lesch et al., 1993, Lesch et al., 1996.
In the mid-1990s, Heils et al. (1996) discovered a 44-base-paired (bp) insertion/depletion polymorphism (5-HTTPR) in the 5′ promoter region of the 5-HTT gene. The 44-bp deletion promoter (S-allele) is less active than the 44-bp insertion promoter (L-allele), resulting in low-level serotonin uptake (Heils et al., 1995). Danielle et al. (2001) hypothesized that the Lgenotype would lead to a depletion of extraneuronal serotonin and increase the risk of aggression in Alzheimer's disease. Robert et al. (2001) reported that cases of Alzheimer's disease with psychotic features and aggression were significantly associated with the 5-HTTPR L/L genotype and increased L allele frequency (Robert et al., 2001). In this study, we hypothesized that both the COMT and 5-HTTPR genotypes might be related to aggressive behavior in Korean schizophrenia patients.
Section snippets
Methods
Unrelated male patients with a diagnosis of schizophrenia (n=168) according to DSM-IV criteria (American Psychiatric Association, 1994) were studied. Diagnoses were made on the basis of semistructured interviews (Endicott and Spitzer, 1978) and supplementary information. The patients were recruited from two psychiatric hospitals. Patients with drug-induced aggressive behavior or a history of alcohol and substance abuse were excluded. The goals of the research and the procedures were explained
Demographic and clinical data
Table 1, Table 2 present demographic data for the subjects. There were no significant differences with regard to age, duration of illness, duration from the latest discharge to readmission, frequency of admission, frequency of outpatient department visits for counseling concerning aggression, education, and marital state across genotypes.
COMT polymorphism
Of the 168 schizophrenic patients, 91 (54.2%) were the COMTH/COMTH type, 64 (38%) were the COMTH/COMTL type, and 13 (7.8%) were the COMTL/COMTL type. The
Discussion
In this study, there was no significant difference in the COMT and 5-HTTPR polymorphisms between the schizophrenia and control groups. This observation is similar to other studies that also reported no association of the COMT and 5-HTTPR polymorphisms with schizophrenia Bonnet-Brilhault et al., 1997, Rao et al., 1998, Tsai et al., 2000, De Chaldee et al., 2001. However, Ohmori et al. (1998) found that the COMTL allele appeared to be associated with susceptibility to schizophrenia. Park et al.
Acknowledgements
The authors thank Dr. H.M. Lachman and Dr. R.D. Strous for help in the preparation of this manuscript.
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2012, Schizophrenia ResearchCitation Excerpt :A common functional single nucleotide polymorphism (SNP) in the COMT gene at codon 108/158, Val158Met (rs4680), generates a valine (Val)-to‐methionine(Met) substitution and results in a fourfold reduction in COMT enzyme activity in the Met/Met homozygotes (Lotta et al., 1995), and increased dopamine levels in the prefrontal cortex. Several studies have shown a strong association between the Met allele and risk for violence in schizophrenia (Han et al., 2004, 2006; Hong et al., 2008; Kotler et al., 1999; Lachman et al., 1998; Strous et al., 1997; Strous et al., 2003; Tosato et al., 2011). In contrast, Jones et al. (2001) reported that Val/Val genotype was associated with greater risk for violence in patients with schizophrenia; others have found the association to be inconsistent (Liou et al., 2001; Koen et al., 2004; Zammit et al., 2004; Kim et al., 2008; Gu et al., 2009).
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