Marja Mattila-Evenden

The DTNBP1 (Dysbindin) Gene Contributes to Schizophrenia, Depending on Family History of the Disease

We have investigated the gene for dystrobrevin-binding protein 1 (DTNBP1), or dysbindin, which has been strongly suggested as a positional candidate gene for schizophrenia, in three samples of subjects with schizophrenia and unaffected control subjects of German (418 cases, 285 controls), Polish (294 cases, 113 controls), and Swedish (142 cases, 272 controls) descent. We analyzed five single-nucleotide polymorphisms (P1635, P1325, P1320, P1757, and P1578) and identified significant evidence of association in the Swedish sample but not in those from Germany or Poland. The results in the Swedish sample became even more significant after a separate analysis of those cases with a positive family history of schizophrenia, in whom the five-marker haplotype A-C-A-T-T showed a P value of.00009 (3.1% in controls, 17.8% in cases; OR 6.75; P=.00153 after Bonferroni correction). Our results suggest that genetic variation in the dysbindin gene is particularly involved in the development of schizophrenia in cases with a familial loading of the disease. This would also explain the difficulty of replicating this association in consecutively ascertained case-control samples, which usually comprise only a small proportion of subjects with a family history of disease.

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.

Determinants of self-rating and expert rating concordance in psychiatric out-patients, using the affective subscales of the CPRS

To investigate in more detail concordance between the recently developed Comprehensive Psychopathological Rating Scale (CPRS) and the recently developed Self‐Rating Scale for Affective Syndromes (CPRS‐S‐A), a total of 101 psychiatric out‐patients were assessed using these procedures and a diagnostic interview according to DSM‐III‐R. Depressive and anxiety syndromes were the most common diagnoses on Axis I. Approximately one‐third of the patients had a diagnosis of clinical personality disorder on Axis II. The majority of the patients were assessed as predominantly manifesting either Cluster B or Cluster C traits. In general, the correlation between self‐and expert‐ratings was strong (0.83 for the Montgomery‐Åsberg Rating Scale (MADRS) depression subscale and 0.76 for the Brief Scale for Anxiety (BSA) anxiety subscale), but it tended to be weaker in the group of patients with clinical personality disorders. The correlation between the two ratings was also weaker in the group with predominantly Cluster B character traits than in the group with predominantly Cluster C traits or the group with no predominant traits, and weaker in the depressive group than in the anxiety group. However, personality disorder diagnoses were over‐represented in the depressive group. The weaker correlations in the groups mentioned above may have been attributable to psychological factors and qualitative differences in cognitive and communicative style. The CPRS‐S‐A is considered to be a useful and reliable instrument for quantitative rating of symptoms in out‐patients. Our results highlight the potential value of using appropriate self‐assessment forms as complementary tools in clinical practice and research.

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 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.

Polymorphism in the serotonin transporter gene and response to treatment in African American cocaine and alcohol-abusing individuals.

The serotonin transporter (5‐HTT) regulates serotonin transmission and modulates behavioral effects of drug of abuse. A polymorphism in the promoter region of the serotonin transporter gene (5‐HTTLPR) yielding a short (S) and long (L) allele has been associated with severity of substance abuse. The aims of the study were to investigate whether 5‐HTTLPR genotypes differed in their response to treatment in cocaine‐ and alcohol‐abusing patients. Polymerase chain reaction‐based genotyping of a 44 base pair insertion/deletion polymorphism was performed in 141 African American cocaine‐dependent patients with concurrent alcohol use who were entering a 12‐week behaviorally oriented outpatient treatment program. In treatment, end of treatment and 6‐month follow‐up outcome measures included changes in Addiction Severity Index (ASI) scores, urine drug screens, days in treatment, individual/group sessions, dropout and completion rates. As expected, there was a reduction in substance abuse by the end of treatment and follow‐up (F = 5.15, p = 0.000). However, there were no differences in the reduction in cocaine use across the LL, LS and SS genotypes. Interestingly, individuals with the S allele showed greater severity of alcohol use at admission (F = 4.84, p = 0.03), and the SS genotype showed less improvement in alcohol measures than the LL at follow‐up (F = 3.68, p = 0.03), after controlling for baseline variables. While we found no association of the 5‐HTTLPR variants with severity of cocaine abuse or any cocaine‐related outcome measures, the data suggested that the 5‐HTTLPR polymorphism may distinguish responders from non‐responders to behavioral treatment in terms of alcohol use. Further investigations are required to determine the role of the 5‐HTTLPR polymorphism in influencing treatment – outcome among substance abusers.

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.