NO ASSOCIATION BETWEEN A POLYMORPHISM IN THE PROMOTER REGION OF THE MAOA GENE WITH ANTISOCIAL PERSONALITY TRAITS IN ALCOHOLICS

G. Koller1,*, B. Bondy1, U. W. Preuss1, M. Bottlender1 and M. Soyka1

1 Psychiatrische Klinik und Poliklinik der LMU München, Nußbaumstraße 7, 80336 München, Germany

Received 9 January 2002; in revised form 15 April 2002; accepted 28 May 2002


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Aims: We analysed the MAOAuVNTR functional polymorphism in the promoter region of the X-chromosomal monoamine oxidase A (MAOA) gene. Genotypes with three-repeat alleles were reported to be associated with antisocial as well as impulsive traits. Methods: The repeat number (3–5) of the MAOA polymorphism was determined in 169 male alcoholic subjects and 72 controls of German descent. Behavioural and personality traits were evaluated using the Brown–Goodwin Assessment for History of Lifetime Aggression, the Buss Durkee Hostility Inventory, as well as the Barrat Impulsiveness Score. A median split in Brown–Goodwin, Buss Durkee Irritability, Buss Durkee Assault and Barrat Impulsiveness Score was conducted. Results: High scores were found, i.e. 47.9% in Brown–Goodwin, 65.7% in Buss Durkee Irritability, 63.3% in Buss Durkee Assault and 59.8% in Barrat Impulsiveness Scale, indicating high impulsiveness, irritability and antisocial behaviour. Based on the results of these questionnaires, we detected no significant differences between the frequency of the three-repeat allele and high or low scores in alcoholics and controls. Conclusions: Taken together, these findings suggest that the three-repeat allele of the MAOAuVNTR 30-bp polymorphism is not associated with impulsive and aggressive personality traits.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Alcohol dependence is a multifactorial disorder probably caused by a complex interaction of genetic and environmental factors (Merikangas, 1990Go; Soyka et al., 2000Go). However, to detect more homogeneous subtypes of alcoholics, the evaluation of clinical and biological parameters is necessary. Previous research defined two subgroups of alcoholics (Cloninger, 1987aGo). While the proposed type 1 is found in both genders and is prone to passive, dependent and anxious behaviour, the type 2 alcoholics are characterized as males, who show more antisocial, impulsive and aggressive behaviour with an early age of onset and a high genetic predisposition (Cloninger, 1987bGo; Von Knorring et al., 1987Go; Babor et al., 1992Go).

In the literature, 30–60% of the variance in many personality traits were described to be inherited (Benjamin et al., 1998Go). Using biological variables to further characterize these subtypes of alcoholics, some evidence is presented in the literature that there might be a correlation between type 2 alcoholism and alterations in the activity of the mitochondrial enzyme monoamine oxidase (MAO) (Devor et al., 1993Go). MAO is involved in the degradation of dietary amines and neurotransmitters, such as serotonin, noradrenaline and dopamine. The enzyme activity is controlled by two genes, MAOA and MAOB, which are located in the chromosomal region of Xp11 (Chen et al., 1992Go). Previous research suggested decreased levels of platelet MAOB as a marker of type 2 alcoholism (Sullivan et al., 1990Go; Rommelspacher et al., 1994Go; Von Knorring et al., 1994Go). However, other research groups reported no differences in platelet MAOB activity between type 1 and type 2 alcoholics (Anthenelli et al., 1998Go).

The MAOA activity was shown to be genetically determined (Devor et al., 1993Go). Two polymorphisms of the MAOA gene in alcoholics were studied: a 30-bp variable nucleotide tandem repeat (VNTR) in the promoter region and a dinucleotide repeat in intron 2 (Manuck et al., 2000Go). In 1998, the functional VNTR polymorphism in the promoter region of the MAOA gene was reported for the first time (Sabol et al., 1998Go). This polymorphism is characterized as a repeat sequence with 3, 3.5, 4 or 5 copies and was designated MAOAuVNTR (MAOA-upstream variable number of tandem repeats). Alleles with three and four repeats are known to be most common.

Alleles with three or five repeats were reported to be less efficient in transcription than the alleles with four repeats (Deckert et al., 1999Go).

Human and animal research has provided some evidence of a relationship between impulsive, aggressive traits and addictive behaviour with alterations of the MAOA gene. In a Dutch family, a mutation in the MAOA gene was linked to a phenotype with impulsive, aggressive, hypersexual and sometimes violent behaviour in each of the five affected males (Brunner et al., 1993Go). Furthermore, aggressive behaviour in male transgenic mice is increased by deletion of the MAOA gene (Cases et al., 1995Go). Between platelet MAOA activity a dinucleotide repeat length polymorphism, a VNTR polymorphism and alcohol and drug dependence associations were reported in a number of different studies (Parsian et al., 1995Go; Vanyukov et al., 1995Go; Hsu et al., 1996Go; Gade et al., 1998Go). The frequency of the low-activity three-repeat alleles of the VNTR polymorphism was reported to be significantly increased in antisocial alcoholics of Caucasian descent compared with control subjects (Samochowiec et al., 1999Go). Another study from the same group reported that the three-repeat allele of the MAOAuVNTR polymorphism might contribute modestly to the dimension of over- and under-reactive behaviours (Schmidt et al., 2000Go). In contrast, in an Australian general population sample no association between this functional polymorphism of the MAOA gene and both depression symptoms and personality traits that predispose to antisocial behaviour was detected (Jorm et al., 2000Go). These different results may be due to ethnic and genetically different populations enrolled in the studies.

In this paper, we report data from a sample of alcoholics in a Caucasian population in which a range of personality traits related to antisocial behaviour was assessed.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Alcohol-dependent subjects
One hundred and sixty nine male patients were recruited from the addiction treatment ward of the psychiatric hospital of the University of Munich, Germany; all patients had been admitted for the treatment of alcohol dependence. All patients were unrelated, of German descent, older than 18 years and met ICD-10 and DSM-IV criteria for alcohol dependence, assessed with the structured clinical interview DSM-IV (SCID, German version; Wittchen et al., 1996Go) and the Semi-Structured Assessment on the Genetics in Alcoholism (SSAGA) (Bucholz et al., 1995Go; Hesselbrock et al., 1999Go). Diagnostic assessment was performed without knowledge of genotype data.

All patients were assessed 2 weeks after admission and after alcohol withdrawal, being free of any psychopharmacological treatment for an average of 1.5 ± 0.6 weeks. Alcohol-dependent patients were excluded if they had a history of any primary major psychiatric disorder or substance dependence other than alcohol or nicotine.

Behavioural assessments
Three instruments were selected for analysis: impulsiveness in alcohol-dependent subjects was assessed using the German version of the Barrat Impulsiveness Scale (Barratt, 1965Go), the Brown–Goodwin Assessment of Lifetime History of Aggression (Brown et al., 1979Go) and the Buss Durkee Hostility Inventory employing Irritability and Assault subscores (Buss and Durkee, 1957Go).

The Barrat Impulsiveness Scale is a self-rating questionnaire with 26 questions concerning control of thoughts and behaviour, structured as a true/false form. A total score was computed. To distinguish between a low and a high impulsiveness subgroup, a median split of the total score was performed. The Brown–Goodwin Lifetime History of Aggression subsumes seven questions concerning aggression expressed towards others (by physical or verbal assault), and antisocial behaviours involving disciplinary action in school or work, with and without police contact. Each question was scored on a 4-point scale. This is also a self-rating questionnaire. A median split of the total score was performed to discriminate between a low and a high score group. The Buss Durkee Hostility Inventory is a widely used self-rating questionnaire structured in a true/false form. To distinguish between a high and a low score group, a median split of total score was conducted.

All questionnaires used were reported to have good internal consistency and test–retest reliability. They were translated and back-translated to be used in a German sample, by two independent members of our research group.

Control subjects
The normal control group consisted of 72 male individuals with a mean age (±SD) of 42.2 ± 13.2 years recruited from a sample of healthy controls. Using {chi}2 statistics, alcoholics and controls did not differ significantly in age. All subjects were white Caucasians of German descent and were not the hospital staff. These subjects were assessed in a similar way to alcohol-dependent subjects.

Ethical standards
Informed written consent was obtained from all patients and controls after complete and extensive description of the study, which was approved by the Ethics Committee of the Ludwig-Maximilians University of Munich in accordance with the principles laid down in the Helsinki Declaration (1964).

DNA analysis
Five millilitre blood samples (EDTA) were collected by venipuncture during routine blood evaluation, and genomic DNA was extracted using standard isolation methods. The 30-bp repeat polymorphism of the MAOA gene promoter region (VNTR) was investigated using the PCR method and primers already published elsewhere (Schmidt et al., 2000Go).

Statistics
Statistics were performed using SPSS Software (Statistical Package for Social Sciences, Version 10.0, 2001; SPSS Inc., Chicago, IL, USA). Differences between subgroups were tested for significance using {chi}2 statistics. Differences between genotype frequencies and questionnaires scores were tested using the {chi}2 test and odds ratios (ORs). Analyses were calculated by comparing the short three-repeat alleles versus the larger four-repeat alleles. A two-tailed type I error rate of 5% was chosen for analyses.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The study included 169 male alcohol-dependent patients. Mean age (± SD) was 41.8 ± 8 years. Mean age of onset was 29.5 ± 9 years with mean years of dependence of 12.4 ± 7 years. Mean daily alcohol intake was 373 ± 196 g. A very small number of subjects (three alcoholics) had the five-repeat alleles. These subjects were not included in the subsequent analysis. With regard to the Brown–Goodwin Assessment History of Lifetime Aggression, 81 of the alcoholics (47.9%) showed low impulsiveness and 81 (47.9%) reported high impulsiveness (missing data from seven patients). In the Buss Durkee Irritability, 43 alcoholics (25.4%) showed low scores and 111 (65.7%) had high scores (missing data from 15 patients). In the Buss Durkee Assault, 48 (28.4%) showed low scores and 107 (63.3%) had high scores. According to the Barrat Impulsiveness Scale, 61 (36.1%) exhibited low impulsiveness scores and 101 (59.8%) high impulsiveness scores.

In all four tests, persons with higher scores showed a lower age of onset of alcoholism (Brown–Goodwin high scorers 26.3 ± 7.8 vs 32.8 ± 10.0 years; Buss Durkee Irritability high scorers 28.9 ± 10.0 vs 31.2 ± 8.4 years; Buss Durkee Assault high scorers 28.7 ± 9.8 vs 31.8 ± 8.9 years; Barrat Impulsiveness Scale high scorers 28.4 ± 8.0 vs 31.5 ± 11.29 years). Using the t-test and the Levene test, differences in age of onset in the Brown–Goodwin (P <= 0.001), Buss Durkee Assault (P = 0.038) and Barrat Impulsiveness Scale (P = 0.031) reached significance (P < 0.05). The difference in the age of onset according to the Buss Durkee Irritability in both low and high scorers did not reach statistical significance (P = 0.19). Alcoholics in our sample with a high score in the Brown– Goodwin Assessment of Lifetime Aggression were found to be more frequently family history-positive (regarding first-degree relatives with alcoholism).

Genotype distribution of the MAOuVNTR polymorphism was nearly the same in alcoholics and controls. In alcoholics, 57 (33.7%) had three repeats, 109 (64.5%) showed four repeats and three (1.8%) showed five repeats. In the control group of 72 persons, 28 (38.9%) showed three repeats and 44 (61.1%) showed four repeats. None in the control group showed five repeats. The genotype frequencies in both groups were almost identical and their differences were not significant using the {chi}2 test (P = 0.453; OR = 1.217).

We compared the high score and low score subgroup from all four tests with the entire control group. No high or low score group was evaluated in the control group. We tested only counts and frequencies of three and of four repeats. We made no comparison of five repeats because of the low amount of five repeats in the alcohol group and their absence from the control group.

When we compared each high and low score subgroup of alcoholics with the complete control group, no differences in the frequency of the three-repeat genotype in alcoholic high scorers in the Brown–Goodwin Assessment History of Lifetime Aggression compared with controls (P = 0.503; OR = 1.273) was detected. Figure 1Go and Table 1Go show the relationship between MAOAuVNTR repeats and Brown– Goodwin score using a scatterplot.



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Fig. 1. Scatterplot of the relationship between MAOAuVNTR repeats and the Brown–Goodwin Score.

 

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Table 1. Number of genotypes (frequencies) of the 30-bp-repeat MAOAuVNTR polymorphism in males according to Brown–Goodwin Assessment History of Lifetime Aggression, Buss Durkee Irritability, Buss Durkee Assault and Barrat Impulsiveness Scale
 
We did not find any significant differences in the frequencies of the three-repeat genotype in patients with high scores in the Buss Durkee Irritability as in the Buss Durkee Assault, compared with controls (Table 1Go) (Buss Durkee Irritability: P = 0.198; OR = 1.551; Buss Durkee Assault: P = 0.754; OR = 1.105). Furthermore, no difference was observed between high scorers in the Barrat Impulsiveness Scores and controls according to the three-repeat genotype (P = 1.000; OR = 0.983).


    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The relationship between the MAOAuVNTR polymorphism and impulsive and antisocial behaviour is controversial. Our results indicate no evidence of an association between impulsive behaviour assessed by Brown–Goodwin, Buss Durkee and Barrat Impulsiveness Scale and the MAOAuVNTR polymorphism. Limitations of our study may be represented by the absence of small or only slight gene effects, but also the way of assessing the phenotype (self-rating questionnaires). Further replication studies are needed to evaluate whether the relationships suggesting the modifying effects of MAOA polymorphism are valid.

Several association studies with the MAOAuVNTR polymorphism have been performed previously (Samochowiec et al., 1999Go; Schmidt et al., 2000Go) with controversial results. In this context, various other instruments were used to measure antisocial and impulsive behaviour. These instruments, such as the SCID II, using the DSM-IV criteria of personality disorders, might be more sensitive to personality and behavioural changes.

Behavioural assessments like the Barrat Impulsiveness Scale, Buss Durkee Hostility Inventory and Brown–Goodwin History of Lifetime Aggression were used in a similar fashion by Manuck et al. (2000)Go. In the latter study, a composite aggression/impulsiveness index, which was significantly lower in the one- and four- (three and five repeats) allele group was derived. In the same study, lifetime aggression (Brown– Goodwin) or hostility (Buss Durkee), similar to our study, were reported as being unassociated with the MAOAuVNTR polymorphism. MAOuVNTR genotypes did not differ significantly on measures of lifetime aggression (LHA) or hostility (BDHI) (Manuck et al., 2000Go). In the same project, only two of three dimensions of the Barrat Impulsiveness Scale were reported to be associated with genotypes of the MAOAuVNTR polymorphism.

Controversial results reported from previous research may also be due to different sample sizes reported in association with studies conducted with the MAOAuVNTR polymorphism. The largest sample size of 850 persons was analysed in a study by Jorm et al. (2000)Go, which presented similar results to those obtained in our study. In both the latter and the present study, no association was found between antisocial personality traits and the MAOAuVNTR polymorphism, using the Barrat Impulsiveness Scale in a similar fashion. Controversial results regarding association studies could be due to differences in the assessment of the phenotype (self-rating, standardized interview, best estimate diagnosis).

The effects of the MAOAuVNTR polymorphism and impulsive behaviour were reported to be very small and no longer significant after Bonferroni correction (Parsian and Cloninger, 2001Go).

There is some evidence from other studies that the MAOAuVNTR polymorphism is related to antisocial behaviour (Schmidt et al., 2000Go). Similar hypotheses are compatible with psychobiological models described previously (Gray, 1987Go; Cloninger et al., 1995Go; Zuckermann et al., 1996Go). Several recent studies have suggested that MAOA gene variants in polymorphic regions are involved in the pathogenesis of addictive behaviour by modulating gene transcription (Vanyukov et al., 1995Go; Hsu et al., 1996Go; Gade et al., 1998Go; Parsian and Cloninger, 2001Go). Our data do not support these observations.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
* Author to whom correspondence should be addressed. Back


    REFERENCES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
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