Kaj Forslund

Central D2-dopamine receptor occupancy in relation to antipsychotic drug effects: a double-blind PET study of schizophrenic patients.

The relationship between central D2-dopamine receptor occupancy and antipsychotic drug effects was examined in a double-blind study. Raclopride was the compound used to induce a selective occupancy of the D2-dopamine receptors. In addition, 11C-labeled raclopride was the radioligand used to measure occupancy by positron emission tomography (PET). Seventeen schizophrenic patients were randomly assigned to one of three parallel groups treated for 4 weeks with daily doses of 2, 6, or 12 mg of raclopride. D2-receptor occupancy was determined by PET at steady-state conditions in 13 patients who completed the study. A statistically significant relationship was demonstrated between antipsychotic effect and degree of D2-receptor occupancy (p < 0.05). Patients with extrapyramidal side effects had significantly higher D2-receptor occupancy than those without (p = 0.02). The finding of a relationship between selective occupancy of the D2-dopamine receptors and clinical effects in schizophrenic patients principally provides new support for the dopamine hypothesis of antipsychotic drug action.

Association between a promoter polymorphism in the dopamine D2 receptor gene and schizophrenia.

Genetic factors and dopamine receptor dysfunction have been implicated in the pathophysiology of schizophrenia. Recently, an association between a putative functional promoter polymorphism (-141C Ins/Del) in the dopamine D2 receptor gene and schizophrenia was reported. We investigated unrelated Swedish schizophrenic patients (n = 129) and control subjects (n = 179) for the same polymorphism. Similarly to a previous Japanese report, the - 141C Del allele frequency was significantly lower in patients than controls (chi2=4.4, 1 df, p<0.05; odds ratio 0.49, 95% confidence interval 0.26-0.91). The present and previous results may indicate that the -141C Ins/Del dopamine D2 receptor gene polymorphism affects susceptibility to schizophrenia.

No association between serotonin transporter gene polymorphisms and personality traits

Human family and twin studies have established considerable heritable components in personality traits as assessed by self-report questionnaires. Recently, an association between a functional polymorphism in the upstream regulatory region of the serotonin transporter gene and neuroticism-related personality traits was reported. Two different serotonin transporter polymorphisms including the previously associated variant were genotyped in two samples of healthy Swedish subjects (n = 127 and n = 178, respectively) assessed with the Karolinska Scales of Personality (KSP) inventory. No statistically significant association between serotonin transporter polymorphisms and any of the eight neuroticism-related KSP scales was found. Thus, the previously reported association between serotonin transporter alleles and neuroticism-related personality traits could not be replicated in the present study.

Association between a promoter variant in the monoamine oxidase A gene and schizophrenia

Monoaminergic transmission has been implicated in the pathophysiology of schizophrenia. We investigated a putative functional promoter polymorphism in the monoamine oxidase A (MAOA) gene in schizophrenic patients (n=133) and control subjects (n=377). In men, there was an association between the less efficiently transcribed alleles and schizophrenia (chi(2)=4.01, df=1, p<0.05). In women, no significant differences were found. The present results support the involvement of the MAOA gene in men with schizophrenia in the investigated Swedish population but should be interpreted with caution until replicated.

Lack of association between dopamine D4 receptor gene and personality traits

BACKGROUND Personality traits have shown considerable heritable components. Association between alleles of a polymorphism in the third exon of the dopamine D4 receptor gene (DRD4) and the personality trait Novelty Seeking has been reported. Recently, in a sample of Swedish non-psychiatric subjects we could not detect any significant relationships between the same polymorphism and Novelty Seeking related scales in the Karolinska Scales of Personality (KSP). However, there was a tendency in the direction of the proposed association. There were also tentative associations between an exon I 13 bp deletion polymorphism and the personality traits Socialization and Guilt. METHODS We investigated a new Swedish population-based sample (N = 167) investigated with the KSP for three DRD4 polymorphisms. RESULTS Neither of the previous results were replicated. Combining the previous and the present samples did not give rise to any significant association between DRD4 polymorphisms and personality scales. CONCLUSIONS The dopamine D4 receptor gene is probably not of importance to the different personality dimensions as measured by the Karolinska Scales of Personality.

Association between a promoter dopamine D2 receptor gene variant and the personality trait detachment

BACKGROUND Personality traits have shown considerable heritable components. Striatal dopamine D(2) receptor density, as determined by positron-emission tomography, has been associated with detached personality, as assessed by the Karolinska Scales of Personality. A putative functional promoter polymorphism in the dopamine D(2) receptor gene (DRD2), -141C ins/del, has been associated with dopamine D(2) receptor density. METHODS In this study healthy subjects (n = 235) who filled in at least one of several personality questionnaires (Karolinska Scales of Personality, Swedish Universities Scales of Personality, Health-relevant Five-factor Personality Inventory, and Temperament and Character Inventory) were analyzed with regard to the DRD2 -141C ins/del variant. RESULTS There was an association (p =.001) between the DRD2 -141C ins/del variant and Karolinska Scales of Personality Detachment scale, indicating higher scores in subjects with the -141C del variant. There were also associations between the DRD2 -141C ins/del variant and a number of Karolinska Scales of Personality and Swedish Universities Scales of Personality Neuroticism-related scales, but of these only Swedish Universities Scales of Personality Lack of Assertiveness scale (p =.001) survived correction for multiple testing. CONCLUSIONS These results add further support for the involvement of dopamine D(2) receptor in certain personality traits. The results should be treated with caution until replicated.

A polymorphic region in the human transcription factor AP-2beta gene is associated with specific personality traits.

Transcription factor AP-2β is implicated in playing an important role during embryonic development of different parts of the brain, eg, midbrain, hindbrain, spinal cord, dorsal and cranial root ganglia.1, 2 The gene encoding AP-2β contains a polymorphic region which includes a tetranucleotide repeat of [CAAA] four or five times, located in intron 2 between nucleotides 12593 and 12612.3 Since the midbrain contains structures important for variables such as mood and personality, we have investigated if the AP-2β genotype is associated with personality traits estimated by the Karolinska Scales of Personality (KSP). Identification of transcription factor genes as candidate genes in psychiatric disorders is a novel approach to further elucidate the genetic factors that, together with environmental factors, are involved in the expression of specific psychiatric phenotypes. The AP-2β genotype and KSP scores were determined for 137 Caucasian volunteers (73 females and 64 males). The personality traits muscular tension, guilt, somatic anxiety, psychastenia and indirect aggression were significantly associated with the specific AP-2β genotype, albeit with significant difference between genders. Based on this result the human AP-2β gene seems to be an important candidate gene for personality disorders. Moreover, the present results suggest that the structure of the intron 2 region of the AP-2β gene is one factor that contributes to development of the constitutional component of specific personality traits.

Excess Tryptophan Hydroxylase 17 779C Allele in Surviving Cotwins of Monozygotic Twin Suicide Victims

Objective: To evaluate the relationship of the tryptophan hydroxylase (TPH) genotype to suicidality by the study of surviving monozygotic (MZ) cotwins of twins who committed suicide. Method: Twenty-four surviving Swedish MZ twins whose MZ cotwins had committed suicide were compared to 158 demographically sampled Swedish general population controls for TPH alleles. We also examined serotonin transporter alleles. Results: The living MZ cotwins of suicide victims had a significantly higher TPH 17 779C allele frequency than controls. No significant difference was observed for serotonin transporter alleles. Conclusion: These results, in a small sample, suggest the possibility that the 17 779C allele of the TPH gene may be associated with an increased risk of suicide. Further studies in larger samples are needed.

A regulatory monoamine oxidase a promoter polymorphism and personality traits

Monoamine oxidase type A (MAOA) has been implicated to be part of mechanisms underlying human temperament and psychiatric disorders. We hypothesised that a functional polymorphism in the 5′ untranslated region of the MAOA gene is associated with specific personality traits. In 371 healthy Caucasians, we estimated personality traits by the use of the Karolinska Scales of Personality (KSP), Scandinavian Universities Scales of Personality, Health-Relevant 5-Factor Personality inventory, Temperament and Character Inventory and the revised NEO Personality Inventory. In the same subjects, we analysed the genotype of a polymorphic region consisting of a variable number of a 30-bp repeat sequence located approximately 1.2 kb upstream of the MAOA gene. After correction for multiple testing, no statistically significant differences between MAOA genotype and personality were observed in men (n = 206) nor in women (n = 165). We conclude that the structure of this MAOA promoter region does not have a large impact on the expression of personality characteristics in the present Swedish population.

Transcription Factor AP-2β Genotype Associated with Anxiety-Related Personality Traits in Women

Attempts to link transmitter system genes to certain aspects of personality have been performed. Several monoamine-related gene variants have been investigated. We previously reported an association between a transcription factor activating protein-2β (AP-2β) variant and anxiety-related personality traits as estimated by Karolinska Scales of Personality (KSP). To confirm this reported association, we have, in the present study, analysed an enlarged group of healthy volunteers (n = 370) with regard to AP-2β genotype and personality traits. For estimation of personality traits, individuals completed 5 different personality questionnaires, i.e. Swedish Universities Scales of Personality (SSP), Health-Relevant 5- Factor Personality Inventory (HP5i), Temperament and Character Inventory, the Revised NEO Personality Inventory and KSP. In contrast to men, women having two long AP-2β alleles displayed lower scores for muscular tension (KSP; F = 10.65, p = 0.0013), somatic trait anxiety (SSP; F = 7.18, p = 0.0081), trait irritability (SSP; F = 4.51, p = 0.032), mistrust (SSP; F = 4.01, p = 0.0468) and negative affectivity (HP5i; F = 10.20, p = 0.0017) than women with at least one short allele. The data presented in this study, together with our previously published data, suggest that AP-2β intron 2 genotype is associated with low levels of anxiety-related personality traits in women. Hence, these data further suggest the human AP-2β gene as a novel candidate gene in personality.