Association of 5-HT1B receptor gene and antisocial behavior in alcoholism

Summary. The 5-HT1B receptor gene has been postulated to play a modulatory role in alcohol consumption and alcohol dependence, and was considered a candidate gene for alcoholism. More recently, the association of the 5-HT receptor gene polymorphism and antisocial personality traits in alcoholism has been discussed. This possible association was studied using material from our gene bank for alcoholism. The research instruments used to phenotype patients were partly adopted from the US Collaborative Study on the Genetics of Alcoholism (COGA) which include anxiety- and depression-related scales from personality inventories such as the temperament and character inventory (TCI), the NEO-Five-Factor Inventory (NEO-FFI) and the Minnesota Multiphase Personality Inventory (MMPI-2). Based on the examination of 164 alcoholic subjects, an association was found between a lower frequency of the 5-HT 1B 861C allele, antisocial personality traits and conduct disorder in alcohol-dependent subjects. Adult antisocial personality occurred more often in males than females. Possible implications of these findings are discussed.     

Association of a regulatory polymorphism in the promoter region of the monoamine oxidase A gene with antisocial alcoholism.

We analyzed a novel functional 30-bp repeat polymorphism in the promoter region of the X-chromosomal monoamine oxidase A gene (MAOA) to test whether length variation of the repeat polymorphism contributes to variation in the individual vulnerability to antisocial behavior and liability to alcohol dependence. The repeat number (3-5) of the MAOA polymorphism was assessed in 488 male subjects of German descent, a sample comprising 185 psychiatrically screened control subjects and 303 alcohol-dependent subjects including 59 alcoholics with antisocial personality disorder. The frequency of the low-activity 3-repeat allele was significantly increased in 59 antisocial alcoholics compared to 185 control subjects (51 vs. 35%; P = 0.031) and to 244 alcoholics without antisocial personality disorder (51 vs. 32%; P = 0.008), respectively. We found no significant difference in the frequency of the 3-repeat allele between 244 alcoholics without an antisocial personality disorder and the control subjects. Our findings suggest that the low-activity 3-repeat allele of the MAOA promoter polymorphism confers increased susceptibility to antisocial behavior rather than alcohol dependence per se in alcohol-dependent males.     

Alcoholism and personality

OBJECTIVE: The search for an alcoholic personality has been pursued with varying enthusiasm throughout the 20th century. This paper reviews the methodological issues, research designs and current theories relating alcoholism and personality. METHOD: A selected literature search using computerised databases was ordered via the four major research design strategies: cross sectional studies, high-risk studies, longitudinal studies and genetic epidemiology studies. RESULTS: Cross sectional studies have suggested that two broad bands of personality, impulsivity/novelty seeking and neuroticism/negative emotionality, are associated with alcoholism. Although high-risk studies have repeatedly shown that sons of male alcoholics are at increased risk of alcoholism, whether this risk is related to personality variables is unclear. Many authors believe that the presence of antisocial personality disorder is a confounder and that this may explain some of the contradictory findings. Longitudinal studies have consistently reported that antisocial behaviour and hyperactivity are related to later alcoholism. Negative emotionality seems to be less important and may largely be a consequence of the alcoholism itself. Genetic epidemiological studies suggest that personality measures play a modest but significant role in the genetic influence of alcoholism. The strongest relationships are with conduct disorder and antisocial behaviour. The postulated alcoholic subtypes (Type I, Type II or Type A/B) based on age of onset and personality style have been challenged by recent research. The most vulnerable to alcoholism may be those with both high impulsivity/high novelty seeking and high neuroticism/negative emotionality. CONCLUSION: Antisocial behaviour and hyperactivity are the most consistent behaviours associated with alcoholism. These behaviours are not specific for alcoholism and are associated with many other psychiatric conditions. Personality variables by themselves explain only a small proportion of the risk for alcohol dependence. There is no alcoholic personality nor are there personality measures which are specific to vulnerability to later alcohol dependence. Attempting to link alcoholism with theoretical, poorly validated models of personality is premature.     

Psychiatric comorbidity and suicidality among intravenous drug users.

BACKGROUND: Prevalence of lifetime psychiatric comorbidity and history of attempted suicide among intravenous drug users was investigated. METHOD: One thousand sixty-two relatives of hospitalized alcoholics, felons, and control subjects were administered a structured interview that gathered data on lifetime psychiatric symptoms and psychoactive drug use. Psychiatric diagnoses were based on interview information, medical records, and family history data. Comparisons were made between 411 subjects who used no illicit drugs, 329 cannabis users, 230 subjects who had used psychoactive drugs other than cannabis more than five times but had never injected drugs, and 92 intravenous drug users. RESULTS: Any history of injecting drugs increased the odds of being diagnosed with antisocial personality disorder by a factor of 21.01, alcoholism by 4.42, and unipolar depression by 3.02. A diagnosis of antisocial personality disorder increased the odds of having injected drugs by a factor of 27.19, while diagnoses of alcoholism or unipolar depression conveyed odds for injecting drugs of 4.62 and 3.70, respectively. Intravenous drug use was associated with an 8.27-fold increase in odds for a suicide attempt compared with no drug use. CONCLUSION: Rates of alcoholism, depression, and antisocial personality disorder, but not other psychiatric disorders (other than drug dependence), are significantly elevated in intravenous drug users. Moreover, among drug users, the decision to inject is differentially made by those with antisocial personality disorder. A history of suicide attempt is common among intravenous drug users, but injecting appears to convey little additional risk above substantial but non-intravenous drug use.     

Association of personality disorders with Type A and Type B alcoholics

Personality disorders frequently occur as comorbid disorder in alcohol–dependent subjects. Antisocial personality was described as an important characteristic in Cloninger's Type 2 and Babor's Type B subjects. The impact of other personality disorders on these alcoholism typologies, their pathogenesis and prognosis is, however, still unclear. The present study investigated the prevalence of personality disorders in 237 (194 males) detoxified alcohol–dependent patients after subtyping this sample according to Babor's Type A/B following the criteria suggested by Schuckit et al. (1995). Personality disorders were assessed with the SCID–II (DSM–IV). In all, 160 patients (68 %) could be classified as Type A, and 77 (32 %) as Type B.Type B subjects were younger, had an earlier onset,more alcohol intake and a more severe course of alcohol dependence. Type B patients had significantly more often any cluster A and B personality disorder, and significantly specifically more often a borderline, antisocial and avoidant personality disorder. There were no statistical differences concerning the other personality disorders. In summary, the Type A/B dichotomy using the criteria of Schuckit et al. (1995) was replicated successfully. Differences concerning cluster B personality disorder prevalence of Type B subjects demonstrated that these subjects are significantly more often affected from borderline and antisocial personality disorder. The impact of other personality disorders does not play a substantial role in subtyping alcoholics.     

A family study of alcohol dependence: coaggregation of multiple disorders in relatives of alcohol-dependent probands

BACKGROUND: Alcohol dependence tends to aggregate within families. We analyzed data from the family collection of the Collaborative Study on the Genetics of Alcoholism to quantify familial aggregation using several different criterion sets. We also assessed the aggregation of other psychiatric disorders in the same sample to identify areas of possible shared genetic vulnerability. DESIGN: Age-corrected lifetime morbid risk was estimated in adult first-degree relatives of affected probands and control subjects for selected disorders. Diagnostic data were gathered by semistructured interview (the Semi-Structured Assessment for the Genetics of Alcoholism), family history, and medical records. Rates of illness were corrected by validating interview and family history reports against senior clinicians' all sources best estimate diagnoses. Sex, ethnicity, comorbidity, cohort effects, and site of ascertainment were also taken into account. RESULTS: Including data from 8296 relatives of alcoholic probands and 1654 controls, we report lifetime risk rates of 28.8% and 14.4% for DSM-IV alcohol dependence in relatives of probands and controls, respectively; respective rates were 37.0% and 20.5% for the less stringent DSM-III-R alcohol dependence, 20.9% and 9.7% for any DSM-III-R diagnosis of nonalcohol nonnicotine substance dependence, and 8.1% and 5.2% for antisocial personality disorder. Rates of specific substance dependence were markedly increased in relatives of alcohol-dependent probands for cocaine, marijuana, opiates, sedatives, stimulants, and tobacco. Aggregation was also seen for panic disorder, obsessive-compulsive disorder, posttraumatic stress disorder, and major depression. CONCLUSIONS: The risk of alcohol dependence in relatives of probands compared with controls is increased about 2-fold. The aggregation of antisocial personality disorder, drug dependence, anxiety disorders, and mood disorders suggests common mechanisms for these disorders and alcohol dependence within some families. These data suggest new phenotypes for molecular genetic studies and alternative strategies for studying the heterogeneity of alcohol dependence.     

Different allele distribution of a regulatory MAOA gene promoter polymorphism in antisocial and anxious-depressive alcoholics

Summary. Heritable factors account for approximately 40–60% of the total variance of liability to alcohol dependence. The present study tested whether a novel functional polymorphism in the promotor region of the X-chromosomal monoamine oxidase A gene (MAOA) was related to antisocial and anxious-depressive traits in alcoholics. Due to the X-chromosomal localization of the MAOA gene, psychobiological traits were compared separately for both genders of 298 male and 66 female alcoholics. In males, 30 of 59 alcoholics with antisocial personality disorder carried the low-activity 3-repeat allele in contrast to only 7 of 31 anxious-depressive alcoholics (51% vs. 23%; p = 0.02). Likewise, female anxious-depressive alcoholics showed a trend towards a low frequency of genotypes with the 3 repeat allele compared to female alcoholics without these symptoms (29% vs. 53%; p = 0.09). Taken together, these findings suggest that the 3-repeat allele of the MAOA polymorphism contributes modestly to the dimension of over- and underreactive behaviors as possible antecedents of alcoholism. Received June 16, 1999; accepted January 25, 2000     

Association in alcoholic patients between psychopathic traits and the additive effect of allelic forms of the CNR1 and FAAH endocannabinoid genes, and the 3' region of the DRD2 gene

Little is known about the genetic factors that underlie the comorbidity between alcohol use disorder and antisocial personality disorder. Previous studies have associated both, dopaminergic and endocannabinoid systems to severe alcoholism with non-adaptive disrupted behaviours. In this work we have examined some gene variants involved in such systems in a sample of alcoholic patients to test whether there is a relationship with antisocial traits. The genetic analysis involved the genotyping of the single nucleotide polymorphism (SNP) TaqIA located nearby the DRD2 gene, the 10-repeat allele of a variable number tandem repeats (VNTR) of the SLC6A3 gene, the C385A FAAH SNP and the 3'-UTR microsatellite of CNR1 gene. The clinical study was performed in 137 Spanish alcohol dependent males. Antisocial Personality Disorder (DSM-IV) diagnosis was made by applying the International Personality Disorder Examination, and psychopathic traits were evaluated by the Hare's Psychopathy Checklist revised (PCL-R). The genotype distribution indicates there is a relationship between the TaqIA SNP, CNR1 and FAAH genes and PCL-R's Factor 1 in alcoholic patients. This relationship seems to be additive and independent and might be responsible for 11.4% of the variance in this PCL-R subscale. Our results suggest the implication of the dopaminergic and endocannabinoid systems in those processes leading to the comorbidity of alcoholism and antisocial behaviour.     

P3 event-related potential amplitude and the risk for disinhibitory disorders in adolescent boys

BACKGROUND: The children of parents who abuse alcohol typically show reduced amplitude of the P3 event-related potential wave. We determined if this effect was present in a population-based sample of older adolescent boys, whether it was associated with paternal antisocial personality and drug use, and whether it appeared in youth with childhood externalizing and substance use disorders. METHODS: A statewide sample of 502 male youth, identified from Minnesota birth records as members of twin pairs, had their P3 amplitude measured, using a visual oddball paradigm when they were approximately 17 years old. Structured clinical interviews covering attention-deficit/hyperactivity disorder, conduct disorder, oppositional defiant disorder, antisocial personality disorder, and substance use disorders were administered in person to the youth and his parents at the time of the P3 assessment and again to the youth 3 years later. RESULTS: Reduced P3 was associated with disorders and paternal risk for disorders, reflecting a behavioral disinhibition spectrum that included attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, antisocial personality disorder, alcoholism, nicotine dependence, and illicit drug abuse and dependence. Reduced P3 at age 17 predicted the development of substance use disorders at age 20. Most effect sizes associated with these group differences exceeded 0.70, indicating medium to moderately large group differences. Maternal alcoholism and substance use during pregnancy were unrelated to P3 amplitude in offspring. CONCLUSION: Small amplitude P3 may indicate genetic risk for a dimension of disinhibiting psychiatric disorders, including childhood externalizing, adult antisocial personality disorder, and substance use disorders.     

Use of health services by men with and without antisocial personality disorder who are alcohol dependent

In a sample of 104 medically stable male veterans with alcohol dependence, rates of health service utilization were compared for 48 patients with a primary diagnosis of antisocial personality disorder and 56 patients without this diagnosis. Patients were diagnosed using DSM-IV lifetime criteria; previous utilization of health services was based on self-reports. Although a similar proportion of both groups reported previous service use, patients with antisocial personality disorder reported using more substance abuse treatment services than those with a primary diagnosis of alcohol dependence. Between-group multiple regression analysis showed that an earlier age at onset of alcoholism and a history of a comorbid substance-induced mental disorder best predicted higher rates of use of substance abuse treatment.     

A functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States

BACKGROUND: Quantitative trait locus studies, and observations in animals manipulated for the neuropeptide Y (NPY) gene suggest that variation within this gene may contribute to alcoholism. A recent population study suggested that the Pro7 allele of a functional NPY polymorphism (Leu7Pro) may be associated with increased alcohol consumption. We tested whether the Pro7 allele is associated with alcohol dependence in European Americans (EA). METHODS: The design was a population study comparing the Leu7Pro allele frequencies in alcohol-dependent subjects and controls. Population stratification potential and diagnostic specificity was studied by genotyping individuals from additional populations and psychiatric diagnostic classes. We studied 2 independently collected samples of EA alcohol-dependent subjects (sample 1, n = 307; sample 2, n = 160) and a sample of psychiatrically screened EA controls (n = 202); 8 population samples, including African Americans and European Americans (total n = 551); and 4 samples of individuals with Alzheimer disease, schizophrenia, posttraumatic stress disorder, and major depression (total n = 502). The main outcome measure was the difference in Leu7Pro allele frequencies between alcohol-dependent subjects and controls. RESULTS: The frequency of the Pro7 allele was higher in the alcohol-dependent subjects (sample 1, 5.5%; sample 2, 5.0%) compared with the screened EA controls (2.0%) (sample 1 vs controls, P=.006; sample 2 vs controls, P=.03). The attributable fraction (excess morbidity) in similarly affected populations, owing to the Pro7 allele, was estimated to be 7.3%. The frequency of the Pro7 allele was equal or lower in the population samples, as compared with the screened EA controls (0%-2.2%), with 1 exception (Bedouins). We found no significant evidence that the association of the Pro7 allele with alcohol dependence was due to an association with a comorbid psychiatric disorder. CONCLUSIONS: These results suggest that the NPY Pro7 allele is a risk factor for alcohol dependence. This is only the second specific genetic mechanism ever identified that modulates risk for alcohol dependence.     

A three-axes approach of subtyping the alcohol dependence syndrome

Subtyping of alcoholics according to specific characteristics has a long tradition in alcoholism research with a number of different typologies that emerged in the literature. The goal of the present study was to test a multidimensional approach of subtyping with characteristics from different axes. Therefore, male inpatients meeting ICD-10 criteria for alcohol dependence were rated on three axes by assessing their degree of sensation seeking (personality axis), age of alcoholism onset (clinical axis) and level of dopamine activity (neurobiological axis). By using a configuration frequency analysis, we identified a subtype that was characterized by high sensation seeking early age of alcoholism onset and high dopamine activity. This subtype, which is in accordance with clinical experience and cannot be explained by antisocial personality disorder, embodied a significantly greater proportion of alcoholics than expected. The result emphasizes the usefulness of multidimensional approaches integrating personality, clinical and neurobiological characteristics.     

Study of impulse-control disorders among alcohol-dependent patients.

BACKGROUND: Impulse-control disorders (ICDs) include intermittent explosive disorder, kleptomania, trichotillomania, pyromania, and pathological gambling. Several studies have suggested that the incidence of pathological gambling is substantially higher in alcoholics than in the general population. The rate of co-occurrence of other ICDs and alcohol dependence has never been systematically investigated. In our study, we assessed the frequency of all ICDs in a population of alcohol-dependent patients. We also examined the possibility that the presence of an ICD can correspond to earlier onset and more severe forms of alcoholism, which have a greater association with antisocial personality. METHOD: All patients hospitalized at our psychiatric unit for detoxification between January and August 1997 met DSM-IV criteria for alcohol dependence and were included in this study. Diagnosis of alcohol dependence was confirmed with the Mini-International Neuropsychiatric Interview. ICDs were investigated using the Minnesota Impulsive Disorders Interview. All patients completed the Michigan Alcoholism Screening Test. RESULTS: Among the 79 patients included in the study, 30 (38.0%) met criteria for an ICD. Included in the study were 19 cases of intermittent explosive disorder, 7 cases of pathological gambling, 3 cases of kleptomania, and 1 case of trichotillomania. Patients with co-occurring ICDs were significantly younger than patients without an ICD (mean age = 40.7 vs. 44.5 years; p = .03). Patients with co-occurring pathological gambling were significantly younger at the onset of alcohol dependence than patients without ICDs (mean age = 19.5 vs. 25.9 years; p = .0008). Pathological gamblers had significantly longer duration of alcohol dependence compared with patients without ICDs (26.0 vs. 17.9 years; p = .02). Patients with co-occurring intermittent explosive disorder had the shortest duration of alcohol dependence of all patients (9.9 years). Prevalence of antisocial personality disorder was no different in patients with or without co-occurring ICDs. CONCLUSION: Thirty-eight percent of the alcohol-dependent patients studied presented with an ICD. Patients with ICDs were younger than those without an ICD. The presence of an ICD was not associated with a specific form of alcohol dependence or with antisocial personality. Co-occurrence of pathological gambling, however, was associated with lower age at onset of alcohol dependence, a higher number of detoxifications, and a longer duration of alcohol dependence than was absence of an ICD.     

Suicide attempts in antisocial alcoholics

The dual diagnoses of alcoholism and antisocial personality are frequently associated with suicide attempts. A group of 94 alcoholics with antisocial personality were divided on the basis of a previous suicide attempt. A variety of symptoms, including depression, alcohol and drug abuse, conduct disorder, and violence were found more frequently in the suicide attempter group as reported on the structured interview. These emotional problems were additionally found to have an earlier onset. The results were consistent with the concept of secondary sociopathy and indicated that higher psychopathology may be associated with suicide behavior.     

Reappraisal of the association between the DRD2 gene, alcoholism and addiction.

We analysed the impact of the TaqI A1 allele of the D2 dopamine receptor gene on the risk for alcoholism, trying to depict three explanations frequently proposed to explain discrepancies in association and linkage studies: that the A1 allele may act as a marker rather than as a vulnerability factor, that stratification biases and unevaluated controls may explain positive results, and that the A1 allele is modifying the phenotype rather than increasing the risk for alcoholism. We thus tested another (dinucleotide STRP) marker within the DRD2 gene, selected a new homogenous sample of 113 alcoholic patients and 49 unaffected controls strictly matched for ethnic origins, and systematically assessed both samples with a semi-structured interview to detect (in both samples) alcohol dependence, but also such related traits as specificities of complications. The frequency of the A1 allele was not significantly different between alcoholics and controls but when comparing different subgroups of alcoholics, the A1 allele was significantly more frequent in alcoholic patients with somatic complications (OR = 3.00, CI[1.37-6.62]), social and professional complications (OR = 2. 72, CI[1.25-5.90]), or with co-morbid dependence (OR = 2.88, 95% IC [1.16-7.15]). The association for co-morbid dependence and somatic complications was also positive when taking into consideration both STRP and TaqIA polymorphisms. The A1 allele does not increase the risk for alcoholism per se in our sample, but may be involved in a related trait which is partially dependent on the diagnosis of alcoholism, through a disequilibrium with another close mutation.     

Impulsive traits and 5-HT2A receptor promoter polymorphism in alcohol dependents: possible association but no influence of personality disorders

OBJECTIVE: Impulsive behavior in alcoholics puts them at serious risk of severer course of disease and has been related to the serotonergic neurotransmission dysfunction. The aim of this study is to investigate the association between impulsive aggression in alcohol dependents with regard to the G-1438A polymorphism in the promoter region of the 5-HT2A receptor gene. Furthermore, we investigated the statistical interaction between 5-HT2A alleles, antisocial personality disorder (APD) and impulsive aggression in alcohol dependents. Alcohol dependents were investigated because these personality disorders and impulsive behavior are very frequent in alcohol dependence anf of clinical relevance. METHODS: One hundred and thirty-five patients of German descent meeting DSM-IV criteria of alcohol dependence were recruited. Blood samples were taken from alcohol dependents to determine 5-HT2A promoter polymorphisms using PCR (polymerase chain reaction) of lymphocyte DNA. Impulsive aggression was assessed using a German version of the Barratt Impulsiveness Scale which was translated and backtranslated. Alcohol dependents were subdivided into low- or high-impulsivity groups using a median split of the Barratt score. APD and borderline personality disorder (BPD) were assessed using the SCID-II interview. RESULTS: The low-impulsivity group was slightly older and showed a later age at alcoholism onset than the highly impulsive group. Alcohol dependents with high impulsive traits showed a significant association with 5-HT2A 1438 A alleles. After excluding alcohol dependents with APD or BPD from the analysis, this association remained significant. Furthermore, no association between APD, BPD and 5-HT2A alleles was noted. CONCLUSIONS: Inpatient alcohol dependents showed a significant association between 5-HT2A A alleles and impulsive traits, independent of the presence of APD or BPD. No association was noted between personality disorders and the polymorphism. This is the first report about an association of 5-HT2A promoter polymorphism and impulsive behavior in alcohol dependents. This finding may refer only to impulsive traits and may be independent of personality disorders in this sample. These results have to be confirmed in larger samples and in healthy control subjects to determine whether this association is of general validity.     

Psychiatric disorders and crime: a study of pretrial psychiatric examinations.

A study of 50 consecutive individuals referred for pretrial psychiatric examination, presumably because of previous psychiatric hospitalization (82 percent), indicated that antisocial personality, alcoholism, or drug dependence was present in 80 percent. Schizophrenia or bipolar affective disorder was seen in about a third of the subjects, usually associated as well, however, with antisocial personality, alcoholism, or drug dependence. There were no significant differences in index crime between those with or without schizophenia bipolar affective disorder. It is concluded that the latter conditions occur in no more than two or three per cent of all felons.     

Sociopathy and psychotherapy outcome

One hundred ten nonpsychotic opiate addicts were randomly assigned to receive paraprofessional drug counseling alone or counseling plus professional psychotherapy. The outcomes of patients who received psychotherapy were examined in terms of their DSM-III diagnoses. Four groups were compared: those with opiate dependence alone (N = 16); opiate dependence plus depression (N = 16); opiate dependence plus depression plus antisocial personality disorder (N = 17); and opiate dependence plus antisocial personality disorder (N = 13). Those with opiate dependence plus antisocial personality disorder alone improved only on ratings of drug use. Patients with opiate dependence alone or with opiate dependence plus depression improved significantly and in many areas. Opiate-dependent patients with antisocial personality plus depression responded almost as well as those with only depression. Antisocial personality disorder alone is a negative predictor of psychotherapy outcome, but the presence of depression appears to be a condition that allows the patient to be amenable to psychotherapy, even though the behavioral manifestations of sociopathy are present.     

Interaction between a functional MAOA locus and childhood sexual abuse predicts alcoholism and antisocial personality disorder in adult women

Women who have experienced childhood sexual abuse (CSA) have an increased risk of alcoholism and antisocial personality disorder (ASPD). Among male subjects, a functional polymorphism (MAOA-LPR, monoamine oxidase A linked polymorphic region) in the promoter region of the monoamine oxidase A gene (MAOA) appears to moderate the effect of childhood maltreatment on antisocial behavior. Our aim was to test whether MAOA-LPR influences the impact of CSA on alcoholism and ASPD in a sample of 291 women, 50% of whom have experienced CSA; we also tested whether haplotypes covering the region where both MAOA and monoamine oxidase B (MAOB) genes are located predict risk of alcoholism and ASPD better than the MAOA-LPR locus alone. Participants included 168 alcoholics (39 with ASPD (antisocial alcoholics) and 123 controls (no alcoholics, no ASPD). Antisocial behavior was also modeled as a continuous trait: ASPD symptoms count. The MAOA-LPR low activity allele was associated with alcoholism (P=0.005), particularly antisocial alcoholism (P=0.00009), only among sexually abused subjects. Sexually abused women who were homozygous for the low activity allele had higher rates of alcoholism and ASPD, and more ASPD symptoms, than abused women homozygous for the high activity allele. Heterozygous women displayed an intermediate risk pattern. In contrast, there was no relationship between alcoholism/antisocial behavior and MAOA-LPR genotype among non-abused women. The MAOA-LPR low activity allele was found on three different haplotypes. The most abundant MAOA haplotype containing the MAOA-LPR low activity allele was found in excess among alcoholics (P=0.008) and antisocial alcoholics (P=0.001). Finally, a MAOB haplotype, which we termed haplotype C, was significantly associated with alcoholism (P=0.006), and to a lesser extent with antisocial alcoholism (P=0.03). In conclusions, MAOA seems to moderate the impact of childhood trauma on adult psychopathology in female subjects in the same way as previously shown among male subjects. The MAOA-LPR low activity allele appears to confer increased vulnerability to the adverse psychosocial consequences of CSA. Haplotype-based analysis of the MAOA gene appeared to strengthen the association, as compared to the MAOA-LPR locus alone. A MAOB haplotype was associated with alcoholism independently from ASPD.     

Association in alcoholic patients between Psychopathic Traits and the additive effect of allelic forms of theCNR1 andFAAH endocannabinoid genes, and the 3′ Region of theDRD2 Gene

Little is known about the genetic factors that underlie the comorbidity between alcohol use disorder and antisocial personality disorder. Previous studies have associated both, dopaminergic and endocannabinoid systems to severe alcoholism with non-adaptive disrupted behaviours. In this work we have examined some gene variants involved in such systems in a sample of alcoholic patients to test whether there is a relationship with antisocial traits. The genetic analysis involved the genotyping of the single nucleotide polymorphism (SNP) TaqIA located nearby theDRD2 gene, the 10-repeat allele of a variable number tandem repeats (VNTR) of theSLC6A3 gene, the C385AFAAH SNP and the 3′-UTR microsatellite ofCNR1 gene. The clinical study was performed in 137 Spanish alcohol dependent males. Antisocial Personality Disorder (DSM-IV) diagnosis was made by applying the International Personality Disorder Examination, and psychopathic traits were evaluated by the Hare’s Psychopathy Checklist Revised (PCL-R). The genotype distribution indicates there is a relationship between the TaqIA SNP,CNR1 andFAAH genes and PCL-R’s Factor 1 in alcoholic patients. This relationship seems to be additive and independent and might be responsible for 11.4% of the variance in this PCL-R subscale. Our results suggest the implication of the dopaminergic and endocannabinoid systems in those processes leading to the comorbidity of alcoholism and antisocial behaviour.