Alexander Strobel

Allelic variation in 5-HT1A receptor expression is associated with anxiety- and depression-related personality traits

Summary. The 5-HT1A receptor plays a critical role in the pathophysiology of anxiety and depression as well as in the mode of action of anxiolytic and antidepressant drugs. Human 5-HT1A gene transcription is modulated by a common C-1016G single nucleotide polymorphism (SNP) in its upstream regulatory region. In the present study, we evaluated the role of the HTR1A-1019 polymorphism in the modulation of individual differences in personality traits by an association study of a sample of healthy volunteers. Personality traits were assessed with two different methods, NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant effect of the HTR1A-1019 polymorphism on NEO Neuroticism with carriers of the G allele showing higher scores than individuals homozygous for the C variant. The effect was primarily due to associations with the Neuroticism facets Anxiety and Depression. Carriers of the G allele also exhibited higher TPQ Harm Avoidance scores. Our findings indicate a role of allelic variation in 5-HT1A receptor expression in the development and modulation of anxiety- and depression-related personality traits.

A neuronal nitric oxide synthase (NOS-I) haplotype associated with schizophrenia modifies prefrontal cortex function

Nitric oxide (NO) is a gaseous neurotransmitter thought to play important roles in several behavioral domains. On a neurobiological level, NO acts as the second messenger of the N-methyl-D-aspartate receptor and interacts with both the dopaminergic as well as the serotonergic system. Thus, NO is a promising candidate molecule in the pathogenesis of endogenous psychoses and a potential target in their treatment. Furthermore, the chromosomal locus of the gene for the NO-producing enzyme NOS-I, 12q24.2, represents a major linkage hot spot for schizophrenic and bipolar disorder. To investigate whether the gene encoding NOS-I (NOS1) conveys to the genetic risk for those diseases, five NOS1 polymorphisms as well as a NOS1 mini-haplotype, consisting of two functional polymorphisms located in the transcriptional control region of NOS1, were examined in 195 chronic schizophrenic, 72 bipolar-I patients and 286 controls. Single-marker association analysis showed that the exon 1c promoter polymorphism was linked to schizophrenia (SCZ), whereas synonymous coding region polymorphisms were not associated with disease. Long promoter alleles of the repeat polymorphism were associated with less severe psychopathology. Analysis of the mini-haplotype also revealed a significant association with SCZ. Mutational screening did not detect novel exonic polymorphisms in patients, suggesting that regulatory rather than coding variants convey the genetic risk on psychosis. Finally, promoter polymorphisms impacted on prefrontal functioning as assessed by neuropsychological testing and electrophysiological parameters elicited by a Go-Nogo paradigm in 48 patients (continuous performance test). Collectively these findings suggest that regulatory polymorphisms of NOS1 contribute to the genetic risk for SCZ, and modulate prefrontal brain functioning.

Dopamine and Cognitive Control: The Influence of Spontaneous Eyeblink Rate and Dopamine Gene Polymorphisms on Perseveration and Distractibility

One fundamental problem of intelligent organisms pursuing goal-directed behavior is how to dynamically regulate the balance between maintenance and flexibility. The authors show that central dopaminergic activity, as indicated by spontaneous eyeblink rate and dopamine gene polymorphisms, plays an important role in the modulation of this balance. Seventy-two young adults were examined. Participants with high blink rates showed increased cognitive flexibility but decreased cognitive stability compared with participants with low blink rates. This pattern of results was even more pronounced for carriers of the DRD4 exon III 4/7 genotype, even though no main effects were found for DRD4 and COMT polymorphisms. Results converge with neuropsychological models that suggest a modulatory role of prefrontal dopaminergic activity for processes of cognitive control.

Tryptophan hydroxylase-2 gene variation influences personality traits and disorders related to emotional dysregulation

Variation in the tryptophan hydroxylase-2 gene (TPH2) coding for the rate-limiting enzyme of serotonin (5-HT) synthesis in the brain modulates responses of limbic circuits to emotional stimuli and has been linked to a spectrum of clinical populations characterized by emotional dysregulation. Here, we tested a set of common single nucleotide polymorphisms (SNPs) in and downstream of the transcriptional control region of TPH2 for association with personality traits and with risk for personality disorders in two cohorts comprising of 336 healthy individuals and 420 patients with personality disorders. Personality dimensions were assessed by the Tridimensional Personality Questionnaire (TPQ) and the revised NEO Personality Inventory (NEO-PI-R). Personality disorders were diagnosed with the Structured Clinical Interview of DSM-IV and were allocated to clusters A, B, and C. Individual SNP and haplotype analyses revealed significant differences in genotype frequencies between controls and cluster B as well as cluster C patients, respectively. In both patient groups, we observed overrepresentation of T allele carriers of a functional polymorphism in the upstream regulatory region of TPH2 (SNP G-703T, rs4570625) which was previously shown to bias responsiveness of the amygdala, a structure critically involved in emotionality. Furthermore, significant effects of TPH2 variants on anxiety-related traits defined primarily by the TPQ Harm Avoidance were found in healthy individuals. The results link potentially functional TPH2 variants to personality traits related to emotional instability as well as to cluster B and cluster C personality disorders. These findings implicate alterations of 5-HT synthesis in emotion regulation and confirm TPH2 as a susceptibility and/or modifier gene of affective spectrum disorders.

Influence of Functional Variant of Neuronal Nitric Oxide Synthase on Impulsive Behaviors in Humans

CONTEXT Human personality is characterized by substantial heritability but few functional gene variants have been identified. Although rodent data suggest that the neuronal isoform of nitric oxide synthase (NOS-I) modifies diverse behaviors including aggression, this has not been translated to human studies. OBJECTIVES To investigate the functionality of an NOS1 promoter repeat length variation (NOS1 Ex1f variable number tandem repeat [VNTR]) and to test whether it is associated with phenotypes relevant to impulsivity. DESIGN Molecular biological studies assessed the cellular consequences of NOS1 Ex1f VNTR; association studies were conducted to investigate the impact of this genetic variant on impulsivity; imaging genetics was applied to determine whether the polymorphism is functional on a neurobiological level. SETTING Three psychiatric university clinics in Germany. PARTICIPANTS More than 3200 subjects were included in the association study: 1954 controls, 403 patients with personality disorder, 383 patients with adult attention-deficit/hyperactivity disorder (ADHD), 151 with familial ADHD, 189 suicide attempters, and 182 criminal offenders. MAIN OUTCOME MEASURES For the association studies, the major outcome criteria were phenotypes relevant to impulsivity, namely, the dimensional phenotype conscientiousness and the categorical phenotypes adult ADHD, aggression, and cluster B personality disorder. RESULTS A novel functional promoter polymorphism in NOS1 was associated with traits related to impulsivity, including hyperactive and aggressive behaviors. Specifically, the short repeat variant was more frequent in adult ADHD, cluster B personality disorder, and autoaggressive and heteroaggressive behavior. This short variant came along with decreased transcriptional activity of the NOS1 exon 1f promoter and alterations in the neuronal transcriptome including RGS4 and GRIN1. On a systems level, it was associated with hypoactivation of the anterior cingulate cortex, which is involved in the processing of emotion and reward in behavioral control. CONCLUSION These findings implicate deficits in neuronal signaling via nitric oxide in moderation of prefrontal circuits underlying impulsivity-related behavior in humans.

Association between the dopamine D4 receptor (DRD4) exon III polymorphism and measures of Novelty Seeking in a German population.

Since the observation of an association between the dopamine D4 receptor (DRD4) exon III polymorphism and the temperament trait of Novelty Seeking,1 replication studies have yielded both positive2–5 and negative6–12 results. This raised the question whether the initial findings must be regarded as false positives.13 However, demographic or methodological differences between studies may have obscured the small effect of the DRD4 polymorphism on Novelty Seeking.14 Examination of clinical or older cohorts may have led to an underestimation of possible associations due to a restricted variation of Novelty Seeking in these cohorts. The use of different questionnaires provides another source of variation. In order to replicate the initial findings as precisely as possible, a cohort of 136 healthy, young volunteers was genotyped, and Novelty Seeking was ascertained using the TPQ.15,16 In addition, further aspects of novelty seeking behavior have been ascertained through additional trait measures. We could observe the reported association between long DRD4 alleles and significantly elevated scores (age- and sex-residualized) on the TPQ-Novelty Seeking total scale as well as on two of the subscales, Exploratory Excitability and Extravagance. The results provide further confirmation for the role of the DRD4 exon III polymorphism in modulation of Novelty Seeking. In addition, the pattern of associations between the polymorphism and other scales suggests that this polymorphism has its effect on exploratory, extravagant, and extraverted, rather than on impulsive and monotony-avoidant subtypes of Novelty Seeking.

Interaction between BDNF Val66Met and Dopamine Transporter Gene Variation Influences Anxiety-Related Traits

The involvement in neural plasticity and the mediation of effects of repeated stress exposure and long-term antidepressant treatment on hippocampal neurogenesis supports a critical role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of affective and other stress-related disorders. A previously reported valine to methionine substitution at amino-acid position 66 (BDNF Val66Met) seems to account for memory disturbance and hippocampal dysfunction. In the present study, we evaluated the impact of the BDNF Val66Met polymorphism on individual differences in personality traits in a sample of healthy volunteers in relation to other common gene variants thought to be involved in the pathophysiology of affective disorders, such as the serotonin transporter promoter polymorphism (5-HTTLPR) and a variable number of tandem repeat polymorphism of the dopamine transporter gene (DAT VNTR). Personality traits were assessed using the NEO personality inventory (NEO-PI-R) and Tridimensional Personality Questionnaire (TPQ). There was a significant DAT VNTR-dependent association between NEO-PI-R Neuroticism and the BDNF Val66Met polymorphism. Among individuals with at least one copy of the DAT 9-repeat allele, carriers of the BDNF Met allele exhibited significantly lower Neuroticism scores than noncarriers. This interaction was also observed for TPQ Harm Avoidance, a personality dimension related to Neuroticism. Our results support the notion that allelic variation at the BDNF locus—in interaction with other gene variants—influences anxiety- and depression-related personality traits.

Same or Different? Clarifying the Relationship of Need for Cognition to Personality and Intelligence:

Need for cognition (NFC) refers to an individual’s tendency to engage in and enjoy effortful cognitive processing. So far, little attention has been paid to a systematic evaluation of the distinctiveness of NFC from traits with similar conceptualization and from intelligence. The present research contributes to filling this gap by examining the relation of NFC to well-established personality concepts (Study 1) and to a comprehensive measure of intelligence in a sample with broad educational backgrounds (Study 2). We observed NFC to be positively correlated with openness, emotional stability, and traits indicating goal orientation. Using confirmatory factor analysis and event-related potentials, incremental validity of NFC and openness to ideas was demonstrated, showing that NFC is more predictive of drive-related and goal-oriented behavior and attentional resource allocation. Regarding intelligence, NFC was more associated with fluid than with crystallized aspects of intelligence. Altogether, the results provide strong support for the conceptual autonomy of NFC.

Psychometrische Eigenschaften und Normen einer deutschsprachigen Fassung der Sensation Seeking-Skalen, Form V

Zusammenfassung. Die Sensation Seeking-Skalen, Form V (SSS-V) sind eines der am haufigsten eingesetzten Inventare zur Erfassung von Sensation Seeking. Allerdings wurden immer wieder geringe interne...

Genetic variation of serotonin function and cognitive control

Although it is widely accepted that serotonin plays a pivotal role in the modulation of anxiety- and depression-related personality traits as well as in the pathogenesis of anxiety disorders and depression, the role of serotonin in cognition is less clear. In the present study, we investigated the involvement of serotonin in cognitive behaviors by examining the impact of genetic variation in key regulators of serotonergic neurotransmission on behavioral measures in a cognitive control task. Eighty-five healthy participants performed a cued continuous performance task (the AX Continuous Performance Task [AXCPT]) and were genotyped for polymorphisms in the transcriptional control regions of the tryptophan hydroxylase 2 gene (TPH2 G-703T; rs4570625) and the serotonin transporter gene (5-HTTLPR). The core result was that individuals lacking the rare TPH2 T allele were not faster than T allele carriers, but committed fewer errors and were less variable in responding. These findings parallel those of a recent study where an enhancement of executive control in individuals without the rare TPH2 T/T genotype was observed. Together with recent evidence that individuals without the T allele exhibit higher scores in anxiety- and depression-related personality traits, our results underscore the role of the TPH2 G-703T polymorphism in the modulation of behavior and raise the intriguing possibility that genetic variants associated with higher negative emotionality may have beneficial effects on some cognitive functions.