Kristina Annerbrink

Catechol O -Methyltransferase Val 158 Met Polymorphism is Associated with Cognitive Performance in Nondemented Adults

The catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine in the prefrontal cortex. In the present study, we examined the effect of a Val158Met polymorphism in the COMT gene on individual differences and changes in cognition (executive functions and visuospatial ability) in adulthood and old age. The participants were 292 nondemented men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula study) tested at two occasions with a 5-year interval. Confirmatory factor analyses were used to test the underlying structure of three indicators of executive functions (verbal fluency, working memory, and Tower of Hanoi). Associations between COMT, age, executive functioning, and visuospatial (block design) tasks were examined using repeated-measures analyses of variance. Carriers of the Val allele (with higher enzyme activity) compared with carriers of the Met/Met genotype (with low enzyme activity) performed worse on executive functioning and visuo-spatial tasks. Individuals with the Val/Val genotype declined in executive functioning over the 5-year period, whereas carriers of the Met allele remained stable in performance. An Age COMT interaction for visuospatial ability located the effect for middle-aged men only. This COMT polymorphism is a plausible candidate gene for executive functioning and fluid intelligence in nondemented middle-aged and older adults.

Catechol O-methyltransferase val158-met polymorphism is associated with abdominal obesity and blood pressure in men.

Catechol O-methyltransferase (COMT) degrades catecholamines and estrogens, both of which are of known importance for cardiovascular risk factors such as obesity and hypertension. The gene coding for COMT contains a val158-met polymorphism that exerts a considerable influence on enzymatic activity. We hypothesized that this polymorphism might influence risk factors for cardiovascular disease. Deoxyribonucleic acid samples and data regarding blood pressure and anthropometry were collected from 240 Swedish men, all 51 years old. Subjects homozygous for the low-activity allele (met) displayed higher blood pressure, heart rate, waist-to-hip ratio, and abdominal sagittal diameter as compared with heterozygous subjects, who in turn displayed higher blood pressure, heart rate, waist-to-hip ratio, and abdominal sagittal diameter than subjects homozygous for the high-activity allele (val). All measured variables were significantly correlated; however, the associations between COMT val158-met and cardiovascular variables, and the association between COMT val158-met and anthropometry, respectively, were partly independent of each other, as revealed by multiple linear regression.

Angiotensin-related genes in patients with panic disorder.

Enhanced respiratory variability and decreased heart rate variability have repeatedly been observed in patients with panic disorder. Prompted by the notion that angiotensin may be involved in the control of respiration, heart rate variability, and anxiety‐like behavior, we investigated the putative association between polymorphisms in three angiotensin‐related genes and panic disorder—angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II (ANG II) receptor type 1 (ATr1) in 72 patients with panic disorder and 504 controls. Allele and genotype distribution of the ATr1 A1166C allele and the AGT M235T did not differ between patients and controls. With respect to the ACE I/D polymorphism, the I allele was found to be more frequent in male (χ2 = 8.042, df = 1, P = 0.005), but not female, panic disorder patients than in controls. The results of this investigation provide preliminary evidence for the suggestion that angiotensin‐related genes may be associated with panic disorder in men.

Influence of comt gene polymorphism on fmri-assessed sustained and transient activity during a working memory task

The catechol O-methyltransferase (COMT) gene—encoding an enzyme that is essential for the degradation of dopamine (DA) in prefrontal cortex (PFC)—contains a single nucleotide polymorphism (val/met) important for cognition. According to the tonic–phasic hypothesis, individuals carrying the low-enzyme-activity allele (met) are characterized by enhanced tonic DA activity in PFC, promoting sustained cognitive representations in working memory. Val carriers have reduced tonic but enhanced phasic dopaminergic activity in subcortical regions, enhancing cognitive flexibility. We tested the tonic–phasic DA hypothesis by dissociating sustained and transient brain activity during performance on a 2-back working memory test using mixed blocked/event-related functional magnetic resonance imaging. Participants were men recruited from a random sample of the population (the Betula study) and consisted of 11 met/met and 11 val/val carriers aged 50 to 65 years, matched on age, education, and cognitive performance. There were no differences in 2-back performance between genotype groups. Met carriers displayed a greater transient medial temporal lobe response in the updating phase of working memory, whereas val carriers showed a greater sustained PFC activation in the maintenance phase. These results support the tonic–phasic theory of DA function in elucidating the specific phenotypic influence of the COMT val158met polymorphism on different components of working memory.

Genetics and personality traits in patients with social anxiety disorder: A case-control study in South Africa

BACKGROUND Social anxiety disorder (SAD) is among the most common of all psychiatric disorders with lifetime prevalence estimates ranging from 7% to 13%. Although there is evidence that SAD has a strong familial basis, there are few studies of potential candidate genes. In addition to a genetic association, there is also the possibility that temperamental risk factors for the disorder may be genetically transmitted. Against this background, our aims were threefold: i.) to compare patients and controls with respect to personality traits, ii.) to genotype a subgroup of these participants to investigate the role of genes encoding components of serotonergic (5-HT) and dopaminergic (DA) pathways in patients with SAD and iii.) to compare differences in temperament dimensions between carriers of different (dominant vs. recessive) alleles for selected polymorphisms in SAD patients. METHODS Sixty-three patients (n=63; 35 male, 28 female) with a DSM-IV diagnosis of generalized SAD and SPIN-scores >18, and age-matched control participants (n=150; 31 male, 119 female) were included in the study. The Temperament and Character Inventory (TCI) was used to measure behaviours associated with specific personality dimensions (i.e. temperament/character). DNA was extracted and genotyped to investigate the role of select candidate genes encoding components in serotonergic and dopaminergic pathways in mediating the development of SAD. To achieve this, the frequency of variants in 5-HT and DA genes was compared between a Caucasian subset of SAD patients (n=41) and a convenience sample of Caucasian controls (n=88), using case-control association analyses. We also investigated the frequency of variants in 5-HT and DA-related genes across temperament characteristics in SAD patients, using analyses of variance (ANOVA). RESULTS Patients scored significantly higher on harm avoidance (p<0.001) but lower on novelty seeking (p=0.04) and self-directedness (p=0.004) compared to controls. In the Caucasian subset, there was a difference between patients and controls in distribution of the 5-HT(2A)T102C polymorphism, with significantly more patients harboring T-containing genotypes (T-containing genotypes: [T/T+T/C] vs. [C/C]) (chi2=7.55; p=0.012). Temperament dimensions did not, however, differ significantly between carriers of different (dominant vs. recessive) alleles for the 5-HT(2A)T102C polymorphism in SAD patients. CONCLUSIONS The results suggest a possible role for the 5-HT(2A)T102C polymorphism in the development of SAD. To date genetic findings in SAD have been inconsistent; nevertheless, serotonergic variants, and their associations with temperaments (e.g. reward dependence) deserve further exploration, in the hope that endophenotypes relevant to SAD can ultimately be delineated.

Association between a functional polymorphism in the progesterone receptor gene and panic disorder in women.

Although genetic factors are known to be important risk factors for panic disorder there is as yet no conclusive data regarding specific gene variants. Prompted by evidence supporting progesterone to influence the pathophysiology of panic disorder, polymorphisms in the progesterone receptor gene, a single nucleotide polymorphism (G331A) and an insertion/deletion polymorphism (PROGINS) were investigated in 72 patients with panic disorder and 452 controls. The frequency of the A-allele of the G331A polymorphism was higher in panic disorder patients than in controls (p = 0.01). When male and female patients were analyzed separately, the association was observed in female patients only (p = 0.0009), with an odds ratio of 3.5. No differences between groups were observed for the PROGINS polymorphism. In conclusion, these data suggest that the G331A polymorphism in the progesterone receptor gene may influence the risk for panic disorder in women.

Panic disorder is associated with the Val308Iso polymorphism in the hypocretin receptor gene.

Background Orexin A and B are neuropeptides influencing, for example, arousal and respiration. Although panic disorder is characterized by both enhanced proneness for arousal and by respiratory abnormalities, the possible influence of orexin-related genes on the risk of developing this disorder has not been studied until now. Methods We have analyzed the Ile408Val polymorphism in the hypocretin receptor 1 (HCRTR1) gene and the Val308Iso (G1246A) polymorphism in the hypocretin receptor 2 (HCRTR2) gene in a sample of 215 panic disorder patients and 454 controls. Results Although the polymorphism in the HCRTR1 did not differ between groups, the Iso allele of the HCRTR2 polymorphism was significantly more frequent in patients than in controls. After the population was divided according to sex, the association between the Iso allele of the Val308Iso polymorphism and panic disorder was observed only in female patients. Conclusion Our results suggest that the HCRTR2 polymorphism may be of importance for the pathophysiology of panic disorder. The results should be regarded as preliminary until replicated in an independent sample. This indicates that further research on the possible role of orexin in panic disorder may prove rewarding.

Paroxetine influences respiration in rats: implications for the treatment of panic disorder

Since hyperventilation and shortness of breath are characteristic features of panic attacks, and since the attacks can be elicited by CO(2) inhalation, an involvement of central or peripheral chemoreceptors in the pathophysiology of panic disorder has been suggested. Prompted by clinical reports suggesting that the susceptibility to spontaneous as well as CO(2)-induced anxiety and hyperventilation is attenuated by serotonin reuptake inhibitors (SRIs), we undertook the present study in order to explore the possible effect of an SRI, paroxetine, on baseline respiration and CO(2)-induced hyperventilation in freely moving Wistar rats. A significant increase in baseline respiratory rate was seen both after 5 and 15 weeks of treatment with paroxetine. CO(2) exposure induced a dose-dependent increase in respiratory rate, but not tidal volume, in both paroxetine-treated rats and controls; this response was reduced after 15 weeks of paroxetine treatment, but not after 5 weeks of treatment. We suggest that an influence on the regulation of respiration may be of importance for the anti-panic effect of SRIs.

Respiratory Responses to Intravenous Infusion of Sodium Lactate in Male and Female Wistar Rats

In patients with panic disorder or premenstrual dysphoria, anxiety attacks can be triggered by intravenous administration of sodium lactate. Since respiratory symptoms, such as hyperventilation and shortness of breath, are characteristic features of spontaneous as well as lactate-induced panic, an involvement of central or peripheral chemoreceptors in this reaction has been suggested. In the present study, we examined to what extent intravenous infusion of sodium lactate influences respiratory parameters in freely moving male and female Wistar rats. Prompted by clinical reports suggesting that the susceptibility to spontaneous and lactate-induced anxiety may be influenced by the menstrual cycle, we also investigated if the effect of lactate on respiration in female rats is estrus cycle-dependent. Male and ovariectomized female rats exposed to sodium lactate displayed a larger increase in respiratory rate than rats given an infusion of saline. In intact female rats, the response to lactate infusion was significantly more pronounced in the diestrus phase than in the proestrus/estrus phase of the cycle. It is concluded that sodium lactate is a respiratory stimulant in rat, and that this effect is influenced by female sex steroids.

Association Between Estrus Cycle-Related Changes in Respiration and Estrus Cycle-Related Aggression in Outbred Female Wistar Rats

Premenstrual dysphoric disorder is characterized by irritability surfacing during the luteal phase of the menstrual cycle, and disappearing shortly after the onset of menstruation. Although the cardinal symptoms of premenstrual dysphoria are different from those of panic disorder, the two conditions share a number of traits indicating that they both may be associated with abnormalities in the regulation of respiration. Both subjects with panic disorder and subjects with premenstrual dysphoria are hence reported to display enhanced respiratory variability, and to experience anxiety when exposed to CO2. In the present study, the possible influence of the estrus cycle on respiratory parameters in outbred female rats of the Wistar strain was investigated. Before being tested with respect to respiration, the rats were subdivided into two groups: those displaying estrus cycle-related variation in aggression, as evaluated using the resident intruder paradigm, and those not showing aggression throughout the cycle. Whereas the former group was found to display higher respiratory rate during the diestrus phase than during the proestrus/estrus phase, no cycle-related variation in respiration was observed in animals not showing cycle-related variation in aggression. The results support previous studies indicating that the estrus cycle exerts an influence on respiration, and suggest that rats prone to cycle-related aggression are more sensitive also to the influence of hormonal cyclicity on respiration. The possible bearing of these findings for the aberration in respiration displayed by subjects with premenstrual dysphoria is discussed.