Genetic variation of the ghrelin signaling system in females with severe alcohol dependence.

INTRODUCTION: Central ghrelin signaling is required for the rewarding effects of alcohol in mice. Because ghrelin is implied in other addictive behaviors such as eating disorders and smoking, and because there is co-morbidity between these disorders and alcohol dependence, the ghrelin signaling system could be involved in mediating reward in general. Furthermore, in humans, single nucleotide polymorphisms (SNPs) and haplotypes of the pro-ghrelin gene (GHRL) and the ghrelin receptor gene (GHSR) have previously been associated with increased alcohol consumption and increased body weight. Known gender differences in plasma ghrelin levels prompted us to investigate genetic variation of the ghrelin signaling system in females with severe alcohol dependence (n = 113) and in a selected control sample of female low-consumers of alcohol from a large cohort study in southwest Sweden (n = 212). METHODS: Six tag SNPs in the GHRL (rs696217, rs3491141, rs4684677, rs35680, rs42451, and rs26802) and four tag SNPs in the GHSR (rs495225, rs2232165, rs572169, and rs2948694) were genotyped in all individuals. RESULTS: We found that one GHRL haplotype was associated with reports of paternal alcohol dependence as well as with reports of withdrawal symptoms in the female alcohol-dependent group. Associations with 2 GHSR haplotypes and smoking were also shown. One of these haplotypes was also negatively associated with BMI in controls, while another haplotype was associated with having the early-onset, more heredity-driven, type 2 form of alcohol dependence in the patient group. CONCLUSION: Taken together, the genes encoding the ghrelin signaling system cannot be regarded as major susceptibility genes for female alcohol dependence, but is, however, involved in paternal heritability and may affect other reward- and energy-related factors such as smoking and BMI.

The clock gene PER2 and sleep problems: association with alcohol consumption among Swedish adolescents.

BACKGROUND: Alcohol abuse is associated with sleep problems, which are often linked to circadian rhythm disturbances. Previous studies have separately examined the effects of mutations in the clock gene PER2 on alcohol consumption and sleep problems. Here we hypothesized that an allelic variation in the PER2 gene is associated with alcohol consumption in interaction with sleep problems among adolescents. METHODS: The Survey of Adolescent Life and Health in Västmanland 2006, a Swedish county, including 1254 students 17-18 years old, was used as a population-representative sample of adolescents. We investigated the PER2 Single Nucleotide polymorphism (SNP) 10870 (A/G) in the cohort together with an assessment of alcohol consumption according to the AUDIT-C questionnaire, and sleep problems using a survey consisting of 18 items. Furthermore, we carried out an exploratory analysis on the PER2 Single Nucleotide Polymorphism 10870 polymorphism in a group of severely alcoholic females. RESULTS: We found a significant association of the SNP 10870 in adolescent boys, where the genotype AA, in the presence of several and frequent sleep problems, was associated with increased alcohol consumption. Among adolescent girls, only sleep problems were related to alcohol consumption. A non-significant trend was observed among the severely alcoholic females, with the G allele being over-represented in the severely alcoholic females group in comparision to the control females. CONCLUSION: These results indicate that PER2 gene variation is associated with alcohol consumption in interaction with sleep problems among Swedish adolescent boys.

Transcription factor AP2 beta involved in severe female alcoholism.

Susceptibility to alcoholism and antisocial behavior exhibits an evident link to monoaminergic neurotransmission. The serotonin system in particular, which is associated with regulation of mood and behavior, has an influence on personality characters that are firmly connected to risk of developing alcoholism and antisocial behavior, such as impulsiveness, and aggression. The transcription factor TFAP2b has repeatedly been shown to be involved in monoaminergic transmission, likely due to a regulatory effect on genes that are fundamental to this system, e.g. monoamine oxidase type A, and the serotonin transporter. Recent research has identified a functional polymorphism in the gene encoding TFAP2B that regulates its level of expression. In the present study we have compared a sample of female alcoholics (n=107), sentenced to institutional care for their severe addiction, contrasted against a control sample of adolescent females (n=875). The results showed that parental alcohol misuse was significantly more common among the alcoholic females, and also that parental alcohol misuse was associated with a reduction in age of alcohol debut. We also addressed the question of whether a functional TFAP2b polymorphism was associated with alcoholism. Results showed that the high-functioning allele was significantly more common among the female alcoholics, compared to the non-alcoholic controls. Furthermore, the results also indicated that psychosocial factors, in terms of parental alcohol misuse, depression or psychiatric disorder, had an influence on the association. It was observed that the genetic association was restricted to the subset of cases that had not experienced these negative psychosocial factors.

Serotonin transporter (5-HTTLPR) and monoamine oxidase (MAOA) promoter polymorphisms in women with severe alcoholism.

The serotonin system is known to play a pivotal role for mood, behaviour and psychic illness as e.g. alcoholism. Alcoholism in both males and females has been associated with polymorphisms in genes encoding for proteins of importance for central serotonergic function. Genotyping of two functional polymorphisms in the promoter region of the serotonin transporter and monoamine oxidase-A, respectively, (5-HTT-LPR and MAOA-VNTR), was performed in a group of women with severe alcohol addiction. A large sample of adolescent females from a normal population was used as controls. A significantly higher frequency of the LL 5-HTT genotype (high activity) was found in female addicts without a known co-morbid psychiatric disorder than in the controls. Genotype of the MAOA-VNTR polymorphism did not differ significantly between addicts and controls. However, within the group of alcoholics, when the patients with known co-morbid psychiatric disorders were excluded, aggressive anti-social behaviour was significantly linked to the presence of the high activity MAOA allele. The pattern of associations between genotypes of 5-HTT-LPR and MAOA-VNTR in women with severe alcoholism differs from most corresponding studies on males.

Aggressive behavior linked to corticotropin-reactive autoantibodies.

BACKGROUND: Altered stress response is characteristic for subjects with abnormal aggressive and antisocial behavior, but the underlying biological mechanisms are unclear. We hypothesized that autoantibodies (autoAbs) directed against several stress-related neurohormones may exist in aggressive subjects. METHODS: Using enzyme-linked immunosorbent assay, we studied whether autoAbs directed against corticotropin (ACTH), alpha-melanocyte-stimulating hormone (alpha-MSH), oxytocin, and vasopressin are present in serum of male subjects with conduct disorder and prisoners with history of violence. Healthy blood donors served as control subjects. RESULTS: Both conduct disorder and prisoners groups displayed strongly increased levels of ACTH-reactive immunoglobulin G (IgG) and immunoglobulin M (IgM) autoAbs compared with control subjects. Levels of oxytocin-reactive IgM autoAbs were slightly increased in both groups of aggressive subjects, whereas levels of vasopressin-reactive IgG and IgM autoAbs were lower only in conduct disorder. No differences in the levels of alpha-MSH-reactive autoAbs were found between aggressive and control subjects. CONCLUSIONS: High levels of ACTH-reactive autoAbs as well as altered levels of oxytocin- and vasopressin-reactive autoAbs found in aggressive subjects may interfere with the neuroendocrine mechanisms of stress and motivated behavior. Our data suggest a new biological mechanism of human aggressive behavior that involves autoAbs directed against several stress-related neurohormones.

The serotonin 2A -1438 G/A receptor polymorphism in a group of Swedish male criminals.

Studies have shown that genetic components to some extent underlie behavioral disorders such as impulsive aggression and violence, and that central serotonergic mechanisms are involved in the development of such behavior. In the present study, we analyzed a polymorphism in the gene encoding the serotonin 2A receptor (5-HT2A -1438 G/A) in a group of Swedish criminals (n=97) and in a group of healthy Swedish blood donors (n=202). The 5-HT2A -1438 GG genotype was lower in the criminal group than in the control group (P=0.034). In accordance with previous results, no associations were found between the 5-HT2A -1438 G/A polymorphism and personality as measured by Karolinska Scales of Personality. Neither were there any associations between the studied polymorphism and the type of crime committed.

Autoantibodies against alpha -MSH, ACTH, and LHRH in anorexia and bulimia nervosa patients.

The hypothalamic arcuate nucleus is involved in the control of energy intake and expenditure and may participate in the pathogenesis of eating disorders such as anorexia nervosa (AN) and bulimia nervosa (BN). Two systems are of particular interest in this respect, synthesizing alpha-melanocyte-stimulating hormone (alpha-MSH) and synthesizing neuropeptide Y, respectively. We report here that 42 of 57 (74%) AN andor BN patients studied had in their plasma Abs that bind to melanotropes andor corticotropes in the rat pituitary. Among these sera, 8 were found to bind selectively to alpha-MSH-positive neurons and their hypothalamic and extrahypothalamic projections as revealed with immunostaining on rat brain sections. Adsorption of these sera with alpha-MSH peptide abolished this immunostaining. In the pituitary, the immunostaining was blocked by adsorption with alpha-MSH or adrenocorticotropic hormone. Additionally, 3 ANBN sera bound to luteinizing hormone-releasing hormone (LHRH)-positive terminals in the rat median eminence, but only 2 of them were adsorbed with LHRH. In the control subjects, 2 of 13 sera (16%) displayed similar to ANBN staining. These data provide evidence that a significant subpopulation of ANBN patients have autoantibodies that bind to alpha-MSH or adrenocorticotropic hormone, a finding pointing also to involvement of the stress axis. It remains to be established whether these Abs interfere with normal signal transduction in the brain melanocortin circuitryLHRH system andor in other central and peripheral sites relevant to food intake regulation, to what extent such effects are related to andor could be involved in the pathophysiology or clinical presentation of ANBN, and to what extent increased stress is an important factor for production of these autoantibodies.

Mental and personality disorders as well as personality traits in a Swedish male criminal population.

The study describes personality traits and the presence of personality disorders and mental disorders in a consecutive series of 130 male prisoners in Swedish jails sentenced for serious criminality. The investigation included a psychiatric examination by means of the Structured Clinical Interview (SCID) as well as information taken from criminal records. Personality assessments were made by means of self-report questionnaires, the Karolinska Scales of Personality (KSP) and the DSM-IV and ICD-10 Personality Disorder Questionnaire (DIP-Q). The most common mental disorders were alcohol and drug abuse/dependence, which were present in 55% of the subjects. Personality disorders, too, were common, being present in 56% of the subjects. In the KSP, high scores were found in scales related to impulsiveness, sensation-seeking, nervous tension and distress, cognitive-social anxiety, hostility and aggression. Very low scores were found in the Socialization scale, reflecting a high degree of psychopathy-related personality traits. Despite the high morbidity, the global level of functioning was unexpectedly high, 66 according to GAF. The male prisoners sentenced for heavy criminality had a high degree of both mental disorders and personality disorders. Furthermore, psychopathy-related personality traits were common.

Low platelet monoamine oxidase activity in Swedish imprisoned criminal offenders.

Numerous studies report a connection between low platelet monoamine oxidase activity (trbc MAO) and personality traits such as impulsiveness and sensation seeking. Generally, criminal offenders constitute a group of individuals that are high in such temperamental characteristics. In this study, we investigated trbc MAO activity in imprisoned criminal offenders and in controls where the confounding factor of smoking was under control. Radiometric MAO assays were performed in 99 male criminal offenders and in 60 non-criminal volunteers. Offenders had significantly lower trbc MAO activity than controls, i.e., 8.8 +/- 3.0 nmol/10(10) platelets/mm and 11.3 +/- 5.1, respectively (p<0.0001). When only smoking individuals were included in the analysis, the difference in trbc MAO was still statistically significant (p<0.05). Based on these data, we suggest that trbc MAO is related to mechanisms predisposing for development of specific personality characteristics that in turn increase vulnerability for criminal behaviour. The results also suggest that low trbc MAO activity in criminal offenders is not an artefact of cigarette smoking.

Personality traits and platelet monoamine oxidase activity in a Swedish male criminal population.

BACKGROUND: A Swedish male criminal population was grouped into personality disorder subgroups and investigated with regard to personality traits and platelet monoamine oxidase (MAO) activity. The main aim of the study was to examine the possibility of a risk factor combination by having low platelet MAO activity as well as belonging to a certain diagnostic DSM-IV axis I (drug abuse in the present series) and/or II subgroup. METHODS: Personality disorders were grouped into clusters according to the cluster system used in DSM-IV axis II. The prisoners were grouped into five subgroups and each subject completed the Karolinska Scales of Personality self-report questionnaire. The comparison group for the personality data comprised 51 non-criminal males from a longitudinal Swedish project. Platelet MAO activity was assessed for the criminals as well as for a control group including 60 non-criminal healthy male Caucasians. For testing the existence of syndromes, a configuration frequency analysis (CFA) was used. RESULTS: The results showed low scores on the socialisation and high scores on the sensation seeking-related traits impulsiveness and monotony avoidance, and the somatic anxiety-related muscular tension in the criminals with any DSM-IV mental disorder, however most markedly in cluster AB and cluster B subjects. In addition, cluster AB subjects had significantly lower platelet MAO activity than controls. Two significant 'types' were found among the criminals: one was characterised by low platelet MAO activity, cluster B personality diagnosis as well as drug abuse disorder diagnosis; and the other by a pattern of normal platelet MAO activity, no cluster B personality disorder and no drug abuse disorder diagnosis. CONCLUSION: The aggregation of certain risk factors in the same individual has been shown to contribute to the development of criminal behaviour.

Risk factors for the neurohumoral alterations underlying personality disturbances.

Numerous studies have shown that MAO-B activity in platelets correlates with specific personality characteristics such as sensation seeking and impulsiveness. Low levels of platelet MAO as well as the personality traits associated with these low levels have been associated with type 2 alcoholism, recurrent criminality and antisocial violent behavior. Platelet MAO has a high degree of heritability and regulation of MAOB gene expression seems to explain most of the inter-individual differences in activity. The transcription factor family AP-2 is an important regulatory factor for neural gene expression and neural development, especially in midbrain structures, including the monoaminergic nuclei. In man, the gene encoding AP-2beta contains a polymorphic region in the second intron, consisting of a variable number of tandem repeats [CAAA](4-5). The long AP-2beta allele has previously been associated with specific personality traits as well as with binge-eating disorder characterized by an impulsive temperament. We have shown that males and females homozygous for the long AP-2beta allele display significantly lower platelet MAO activity compared to subjects with one or two short alleles. Thus, we find it likely that the personality disturbances previously linked to low platelet MAO activity could be associated with the presence of two long alleles of the AP-2beta gene. We suggest that the molecular mechanisms underlying the association between platelet MAO and vulnerability, e.g. substance abuse, may involve specific transcription factors that regulate the expression of midbrain monoamine structures as well as that of platelet MAO.