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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Alcohol Clin Exp Res. Author manuscript; available in PMC Oct 27, 2009.
Published in final edited form as:
PMCID: PMC2768292
NIHMSID: NIHMS145328

Effects of MAOA-Genotype, Alcohol Consumption, and Aging on Violent Behavior

Abstract

Background

Environmental factors appear to interact with a functional polymorphism (MAOA-LPR) in the promoter region of the monoamine oxidase A gene (MAOA) in determining some forms of antisocial behavior. However, how MAOA-LPR modulates the effects of other factors such as alcohol consumption related to antisocial behavior is not completely understood.

Methods

This study examines the conjunct effect of MAOA-LPR, alcohol consumption, and aging on the risk for violent behavior. Recidivism in severe impulsive violent behavior was assessed after 7 to 15 years in a sample of 174 Finnish alcoholic offenders, the majority of whom exhibited antisocial or borderline personality disorder or both, and featured impulsive temperament traits.

Results

The risk for committing new acts of violence increased by 2.3% for each kilogram of increase in yearly mean alcohol consumption (p = 0.004) and decreased by 7.3% for every year among offenders carrying the high activity MAOA genotype. In contrast, alcohol consumption and aging failed to affect violent behavior in the low activity MAOA genotyped offenders. MAOA-LPR showed no main effect on the risk for recidivistic violence.

Conclusions

Violent offenders carrying the high activity MAOA genotype differ in several ways from carriers with the low activity MAOA risk allele previously associated with antisocial behavior. Finnish high activity MAOA genotyped risk alcoholics exhibiting antisocial behavior, high alcohol consumption, and abnormal alcohol-related impulsive and uncontrolled violence might represent an etiologically distinct alcohol dependence subtype.

Keywords: Psychiatric Genetics, Alcoholism, Antisocial Personality Disorder, Borderline Personality Disorder, Violent Behavior

Despite the immense burden of alcoholism and violence on society, their etiology remains largely unknown (Ducci and Goldman, 2008; Goldman et al., 2005; Nelson and Trainor, 2007). Alcoholism and violence frequently coexist particularly in early onset alcoholism with antisocial personality disorder (ASPD), which appears to represent a homogeneous subtype of alcoholism (Linnoila et al., 1989; Tiihonen et al., 1993).

Temperament traits have also been associated with alcoholism (Hesselbrock and Hesselbrock, 1992). Both novelty seeking (Grucza et al., 2006; Kampov-Polevoy et al., 2004)—including a subscale of impulsiveness—and harm avoidance (Cloninger, 1987) are robustly associated with alcoholism (Belfer et al., 2006; Ducci et al., 2007; Enoch et al., 2006). Alcoholism is thought to lead to increased impulsiveness and risk for impulsive violence (Babor, 1996; Brewer and Swahn, 2005; Johansson et al., 1999; Zhang et al., 1997). Trait impulsiveness, alcoholism, and violence form a vicious circle that may lead to habitual violence.

Monoamine oxidase A (MAOA) is an outer membrane mitochondrial enzyme that catabolizes monoamines such as serotonin, noradrenalin, and dopamine (Shih et al., 1999). The MAOA gene is located on the X chromosome (Xp11.23-11.4) (Levy et al., 1989). A common polymorphism in the MAOA gene’s transcriptional control region [“MAOA-linked polymorphism region” (MAOA-LPR)] affects transcriptional activity, resulting in high activity or low activity MAOA (Denney et al., 1999; Sabol et al., 1998). Alleles (2, 3, 3.5, 4, 5 or 6) vary in the number of copies of a 30-bp repeat sequence; the 4- (high activity) and 3-repeat (low activity) alleles are the most common. The impact of MAOA genotype on serotonin metabolism is unclear but according to one hypothesis, MAOA activity is presumed to correlate inversely with CNS monoamine metabolites. To date, however, inverse correlations has been observed only between lumbar cerebrospinal fluid homovanillic acid (CSF HVA) and high activity MAOA (Ducci et al., 2006) and between CSF 3-methoxy-4-hydroxyphenylglycol and the low activity variant (Sjoberg et al., 2008), both findings in Finnish male alcoholic offenders, but not between 5-hydroxyindoleacetic acid (5-HIAA) and MAOA-LPR. Recently, women carrying the low activity allele at the MAOA-LPR locus have been found to display lower 5-HT1A receptor availability measured by positron emission tomography indicating higher serotonergic level as compared to women with the high activity genotype. However, a trend in the opposite direction was found among men (Mickey et al., 2008).

Brunner and colleagues (1993) reported a rare point mutation of the MAOA gene in a Dutch family that affected several males by a syndrome of borderline mental retardation, abnormal sexual behavior, and aggressive behavior that tended to cluster in periods of 1 to 3 days, during which the affected male would suffer from insomnia. Later research supports the hypothesis that low activity MAOA (a hyperserotonergic state comparable to Brunner’s point mutation finding) is linked to aggression and violent behavior (Buckholtz and Meyer-Lindenberg, 2008; Caspi et al., 2002; Widom and Brzustowicz, 2006). Some other research, on the other hand, supports an association of the high activity MAOA genotype and impulsive aggression (Beitchman et al., 2004; Manor et al., 2002; Manuck et al., 2000). Altogether, both MAOA genotypes may contribute to aggression and violence (Nelson and Trainor, 2007).

The role of MAOA in determining vulnerability to alcoholism is also unclear due to contradictory results obtained in widely differing samples. An association of the low activity MAOA genotype with alcoholism has been reported by some studies (Guindalini et al., 2005; Parsian and Cloninger, 2001; Parsian et al., 2003; Samochowiec et al., 1999; Schmidt et al., 2000). Other studies failed to find a genotype main effect, but found that the low activity allele increased risk for alcoholism only among subjects exposed to environmental stressors (Ducci et al., 2008; Nilsson et al., 2007a; Vanyukov et al., 2007). On the other hand, other studies have reported an association of the high, rather than low, activity MAOA genotype with alcoholism (Gade et al., 1998) and alcohol-related problem behavior after exposure to psychosocial stressors (Nilsson et al., 2007b).

The sample at hand comprises impulsive-aggressive alcoholics, the majority of whom committed impulsive homicides. Their psychiatric morbidity and their violent acts match those of the majority of Finnish violent offenders (Tiihonen and Hakola, 1994).

The primary aim of the current report was to evaluate the role of MAOA-LPR, alcohol consumption, and their conjunct effect on risk for committing new acts of violence among risk alcoholics. We hypothesized that heavy drinking associates with increased risk for recidivistic violent behavior especially among high activity MAOA genotyped violent offenders as the disinhibitory effect of alcohol might increase the risk of impulsive-aggressive behavior associated with low CSF 5-HIAA in similar samples (Linnoila et al., 1983; Virkkunen et al., 1989, 1994). Secondly, we examined the conjunct effect of MAOA-LPR and age on risk for recidivistic acts of violence. We failed, however, to find studies examining a possible connection between MAOA-LPR, age, and violence but it has been suggested that MAOA expression may decrease over time in mice (Vitalis et al., 2002). Assuming that high activity MAOA genotyped subjects have low central serotonin levels with corresponding low CSF 5-HIAA levels then a decrease in MAOA activity over time might elevate central serotonin levels and decrease impulsive-aggressive behavior among these subjects.

MATERIALS AND METHODS

Subjects

The sample under study included 174 Finnish violent alcoholic offenders recruited between 1990 and 1998. These subjects, due the violent nature of their crimes, were remanded to a mental status examination and spent 2 months in the inpatient care unit of the Department of Psychiatry, Helsinki University Central Hospital. This sample included many subjects who participated in several genetic studies on violent alcoholic offenders, mainly with ASPD (Belfer et al., 2006, 2007; Enoch et al., 2006; Xu et al., 2007). Psychosis and an IQ of less than 70 served as exclusion criteria. Mean age at the time of evaluation was 32.5 years (SD ± 9.7), and mean IQ (WAIS) was 97.2 (SD ± 14.5). The majority of the offenders belonged to lower socio-economic groups. Their occupational status included mainly semi-skilled workers, and many were unemployed at the time of recruitment in the study.

Psychiatric Assessment

Each subject was interviewed with the Structured Clinical Interview for DSM-III-R (Spitzer et al., 1990) to detect lifetime mental disorders (APA, 1987). Interviewers were experienced licensed psychiatrists, and diagnoses were double-checked by psychiatrists at the National Institute of Alcohol Abuse and Alcoholism in Bethesda, Maryland. Axis II diagnoses were as follows: ASPD (61; 36%), borderline personality disorder (BPD) (21; 12%), ASPD and BPD comorbidity (46; 26%), narcissistic personality disorder (8; 5%), paranoid personality disorder (24; 14%), and others (21; 12%). Alcohol dependence was diagnosed in 134 subjects (77%) and alcohol abuse in 40 (23%). Early onset conduct disorder was diagnosed in 42% (73/174) of the subjects. Alcoholics included in this study displayed high level of impulsivity and novelty seeking (as measured with Tridimensional Personality Questionnaire) (Tikkanen et al., 2007).

Alcohol Consumption

Alcohol consumption was measured before the follow-up with the Lifetime Drinking History (Skinner and Sheu, 1982) questionnaire, which is a structured interview where subjects are asked about patterns of alcohol consumption from the first year of regular drinking to the present. We divided the subject’s lifetime alcohol exposure by the number of years of drinking to form a variable describing the lifetime yearly mean alcohol consumption.

Assessment of Violent Behavior

The base line violent offenses were generally serious, impulsive, and committed under the influence of alcohol [alcohol-intoxication occurred in 155/174 cases (89%)]. Impulsive-aggressive behavior was assessed from mental status examination reports, where the offender’s ability to control his behavior during the violent act was thoroughly discussed. One-hundred fifteen (66%) crimes were clearly impulsive and unexpected. A common subjective experience reported by the offenders was that of amnesia and loss of behavioral control during the act of violence. The most common offenses were manslaughter, attempted manslaughter, assault, or battery (61%), murder or attempted murder (19%), arson (16%), and rape (4%). Recidivism in violent behavior was assessed using register data provided by the Legal Register Centre in August 2005. The distribution of the outcome acts of violence was manslaughter, attempted manslaughter, assault, or battery (81.2%), murder or attempted murder (7.3%), arson (7.3%), and rape (4.3%).

The total follow-up period (from enrolment in the study to the examination of criminal records) was 11.7 years (140 months, range 85–182). We subtracted the time spent in prison from the total follow-up time, which resulted in a nonincarcerated follow-up period of 8.1 years (97 months, range = 3–182).

MAOA-LPR Genotyping

The MAOA-LPR was genotyped with PCR primer sequences: Forward 5′-(CCC AGG CTG CTC CAG AAA CATG 3)-3′ and Reverse 5′-(GTT CGG GAC CTG GGC AGT TGT G)-3′. Owing to the high GC content in the region where the MAOA-LPR is located, amplification was performed using Invitrogen’s PlatinumTaq and PCRX Enhancer System kits according to the manufacturer’s protocol (Invitrogen, Carlsbad, CA). A detailed description of the genotyping method appears in the paper by Ducci and colleagues (2006).

As the study sample comprised only males, genotypes were grouped by relative transcriptional activity into 2 categories: high activity (4 repeats, 56%) versus low activity (3 repeats, 44%). These 2 alleles accounted for 97% of the MAOA-LPR variety among the offenders.

Statistical Analyses

Bonferroni- and age-corrected general linear model univariate analyses were conducted for comparison of alcohol consumption means for the whole sample, recidivistic versus nonrecidivistic offenders stratified by MAOA-LPR, and for the examination of interactive effect between MAOA-LPR and recidivism. The risk for acts of violence in the whole sample and in the MAOA-LPR groups was assessed separately by applying forced multivariate logistic regression analyses with MAOA-LPR, alcohol consumption, and aging as independents. The level of significance was set at 95% CI. Analyses were performed with SPSS 15.0 for Windows.

RESULTS

Alcohol Consumption

A bonferroni- and age-corrected general linear univariate model with a good fit (Levene’s statistics F = 2.0, df = 3, df = 151, p = 0.125) suggested that the recidivistic offenders drank 36% more than did the nonrecidivists: 61 kg (SE = 4.7) versus 45 kg (3.8), mean difference 16 kg (p = 0.008). Comparison between the high and low activity MAOA genotyped offenders showed borderline significance (F = 3.7, df = 1, p = 0.056) toward greater alcohol consumption among high activity MAOA genotyped offenders: 59 kg (SE = 3.9) versus 47 kg (4.5), mean difference 12 kg. This model suggested an interaction (F = 4.2, df = 3, p = 0.043) between MAOA-LPR and recidivistic offenses for alcohol consumption.

Figure 1 displays that the high activity MAOA genotyped recidivists emerged as heavy drinkers with significantly greater consumption than that of the other groups. No other pairwaise group comparisons were significant. The all-offender mean consumption was 52 kg (SD ± 38).

Fig. 1
The yearly mean consumption of alcohol (ETHO kilograms per year) in recidivistic and nonrecidivistic offenders stratified by monoamine oxidase A (MAOA) genotype. MAOA-H = high activity genotype, MAOA-L = low activity genotype. Bonferroni corrected comparisons ...

The Effect of MAOA-LPR, Alcohol Consumption, and Aging

MAOA genotype showed no main effect on risk for violent behavior in the first multivariate logistic regression model, whereas alcohol consumption and aging both influenced the risk in opposite directions (Table 1). This model explained 12% (R2 = 0.117) of the risk and no interaction occurred (b = 0.58, SE = 0.67, W = 0.76, df = 1, p = 0.385). The second analysis carried out among the high activity MAOA offenders augmented the pattern observed in the first analysis (Table 1). This model explained 24% (R2 = 0.244) of the risk, and no interaction emerged (b = 0.84, SE = 0.91, W = 0.85, df = 1, p = 0.357). Finally, we applied the original regression model to the low activity MAOA group, but found no effect.

Table 1
The Effect of Alcohol Consumption and Aging on the Risk for New Acts of Violence Among Alcoholic Violent Offenders

Because both alcohol consumption and aging predicted acts of violence in the high activity MAOA genotyped offenders, we attempted to describe the united risk by creating a risk index (Fig. 2). Moreover, because the second logistic regression model failed to show any interaction between these variables and the mean values used to define the index score were centered, we judged that the united risk of drinking and aging was additive.

Fig. 2
A risk index for recidivistic violent behavior among high activity MAOA genotyped offenders. The index composes the variables age and alcohol consumption. The index score 100 was defined as the all-offender means of the variables (age 33 and an alcohol ...

DISCUSSION

Our results show that MAOA-LPR, alcohol consumption, and aging may play an important role in the prediction of impulsive violence. Our results suggest that the high activity MAOA genotype modulates the effect of alcohol consumption and aging on risk for recidivistic acts of violence in a sample of violent Finnish criminal alcoholics.

The group of violent offenders that committed a new violent offense in the 8 year follow-up had a history of significantly larger alcohol exposure than the nonrecidivists. That alcohol exposure correlated with recidivistic violence may depend on the fact that this potent neurotoxic substance causes loss of behavioral control, which has been suggested as a core symptom of addiction (Baler and Volkow, 2006; Goldstein and Volkow, 2002). Research has suggested dysfunction of the inhibitory pathway (Taber et al., 2000; Volkow et al., 1993) and glucose metabolism of the frontal cortex (Bufkin and Luttrell, 2005; Volkow et al., 1994) among alcoholics, which may predispose to loss of behavioral control. Antisocial alcoholic offenders also have an abnormal energy substrate metabolism (Virkkunen et al., 2007) and they tend to neglect nutrition during relapses, which may worsen the glucose metabolism disturbance and increase the risk for uncontrolled impulsive violence.

Analyses suggest that alcohol consumption predicts violent behavior. However, alcohol exposure predicted violence only among high activity MAOA offenders. This result may find support from research claiming that high activity MAOA individuals are more impulsive as compared with low activity MAOA genotyped individuals (Gade et al., 1998; Manor et al., 2002; Manuck et al., 2000). Recent task-related brain imaging studies in healthy males also suggest that high activity MAOA allele carriers exhibit impulsive behavior associating to focal brain activation (Cerasa et al., 2008; Passamonti et al., 2006) and self-reported impulsivity (Passamonti et al., 2006). The high MAOA activity associated impulsive-aggressive violent behavior observed in our alcoholic sample matches indirectly previous consistent research that links low CSF 5-HIAA to impulsive-aggressive behavior (Linnoila et al., 1983; Virkkunen et al., 1989, 1994), suicides (van Praag, 1983; Traskman et al., 1981), and type II alcoholism (Fils-Aime et al., 1996). However, our finding contrasts research that links low activity MAOA with violence and aggression (Brunner et al., 1993; Buckholtz and Meyer-Lindenberg, 2008; Caspi et al., 2002; Widom and Brzustowicz, 2006). This discrepancy may depend on the difference in impulsivity, alcohol consumption, and environmental effects.

The low activity MAOA carriers in our sample entirely comprising violent offenders may have developed aggressive antisocial behaviors for reasons other than those of the high activity MAOA individuals. For instance, the low activity MAOA individuals seem to be vulnerable to adverse childhood experiences (Caspi et al., 2002; Nilsson et al., 2006; Widom and Brzustowicz, 2006). It is thus possible that the effects found amongst high activity MAOA individuals in the present study should be interpreted as representative of individuals who (unlike MAOA low activity individuals) develop alcoholism and antisocial behaviors for reasons other than childhood adversity (Baler et al., 2008). Information on early-life events could possibly have shed further light on this but such data were not available. Low activity MAOA has been associated with personality traits of anger, aggression, hostility, hypersensivity to social exclusion, and increased neural activity in emotion processing areas of the brain (Alia-Klein et al., 2008; Buckholtz and Meyer-Lindenberg, 2008; Buckholtz et al., 2008; Eisenberger et al., 2007). Such traits may lead to some form of aggressive and violent behavior. For instance, Alia-Klein and colleagues (2008) described the low activity MAOA associated self-reported aggression as “… attitudes, values, and beliefs that are consistent with approval of the use of physical violence.” However, when this aggression tendency, linked to the low activity MAOA genotype, leads to violent behavior it may be different from the mainly impulsive, unexpected, and uncontrolled violence observed in the current report.

Possible gene by gene interactions may explain as to why the high activity MAOA recidivists in our sample featured persistent heavy drinking, as emerging evidence shows that antisocial alcoholism associates with abnormal genotypes (Belfer et al., 2006, 2007; Enoch et al., 2006; Xu et al., 2007). Recently, single nucleotide polymorphisms in the GABA receptor alpha2-subunit have been associated with variance in body sway and motor coordination during alcohol-intoxication (Lind et al., 2008). It is conceivable that such polymorphisms, affecting motor control, may interplay with MAOA-LPR if a subpopulation of high activity MAOA alcoholics exhibit impulsive and uncontrolled violence under the influence of alcohol as suggested in the current report. Moreover, epigenetic influence may moderate the conjunct effect of MAOA-LPR and excessive alcohol exposure as various physiological functions are altered in impulsive-aggressive ASPD and BPD (Brewer-Smyth et al., 2004; Lindberg et al., 2003a,b; McBurnett et al., 2000; New et al., 2007; Popma et al., 2007; Sjoberg et al., 2008; Virkkunen et al., 2007).

Aging showed a 7.3% decrease in the risk for recidivism among high activity MAOA offenders for every year, but failed to affect the risk among low activity genotyped offenders. Aging may decrease impulsive-aggressive behavior particularly among high activity MAOA genotyped offenders, if aging decreases MAOA expression in humans, as suggested in mice (Vitalis et al., 2002), possibly resulting in a correction of low central serotonin levels over time which would decrease impulsive-aggressive behavior. Moreover, aging may modulate the effects of some other risk factors especially among the high activity MAOA genotyped offenders. It is possible that our results are biased because we lack data on participation in addiction treatment programs that the Finnish prisons offer. Finding a firm spouse, embracing a religious faith, or attending Alcoholics Anonymous meetings could also decrease alcohol consumption and the risk for uncontrolled impulsive violent behavior over time.

A considerable limitation of our study-setting is that we assessed impulsivity and acute alcohol-intoxication of the index crimes, and lifetime alcohol exposure at the beginning of the follow-up, but we had no data on these variables related to the outcome violent crimes. However, our sample comprises violent offenders and violent crimes that match the bulk of Finnish violent offenders and violent crimes, which are mainly committed under the influence of alcohol, which argues for the alcohol-intoxication related impulsivity of the recidivistic offenses. Moreover, even though we had no access to detailed police reports on the recidivistic offenses, the criminal records revealed that the outcome violent crimes were even more frequently impulsive (manslaughter, attempted manslaughter, assault, or battery) than the index crimes preceding the follow-up (an increase from 61% to 81%). Despite the limitations of this study, we present preliminary results of the conjunct effects of MAOA-LPR, alcohol consumption, and aging on the risk for violent behavior. The main strengths of our study were its large sample size, long prospective follow-up, and reliable register-based outcome measure of dominantly impulsive violence. Results imply that for secondary prevention of violence, the high activity MAOA offenders in particular, should be supported to abstinence and possibly psychopharmacological treatment to increase central serotonin levels. Results are preliminary and need replication in similar populations.

Acknowledgments

We thank the Legal Register Centre for contribution of register data. Ms. Aija Räsänen deserves our gratitude for her diligent secretarial assistance.

Footnotes

FINANCIAL DISCLOSURES AND GRANTS This research benefited from the support of the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, NIH, and a postdoctoral grant from the foundation Olle Engkvist Byggmästare to RLS. Jari Tiihonen has been a faculty member of the Lundbeck International Neuroscience Foundation since 1997, a consult/expert member of Advisory Board of Janssen-Cilag since 2006, a member of Eli Lilly Advisory Board since October 2006, has done research collaboration with Organon since 2007, and has received lecture fees from Janssen-Cilag, Eli Lilly, and Lundbeck. All other authors report no competing interests. No financial support was received from anyone benefiting from these results.

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