| 1. |
- Andersson, Evelyn, et al.
(författare)
-
Genetic Polymorphisms in Monoamine Systems and Outcome of Cognitive Behavior Therapy for Social Anxiety Disorder
- 2013
-
Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectiveThe role of genetics for predicting the response to cognitive behavior therapy (CBT) for social anxiety disorder (SAD) has only been studied in one previous investigation. The serotonin transporter (5-HTTLPR), the catechol-o-methyltransferase (COMT) val158met, and the tryptophan hydroxylase-2 (TPH2) G-703Tpolymorphisms are implicated in the regulation of amygdala reactivity and fear extinction and therefore might be of relevance for CBT outcome. The aim of the present study was to investigate if these three gene variants predicted response to CBT in a large sample of SAD patients.MethodParticipants were recruited from two separate randomized controlled CBT trials (trial 1: n = 112, trial 2: n = 202). Genotyping were performed on DNA extracted from blood or saliva samples. Effects were analyzed at follow-up (6 or 12 months after treatment) for both groups and for each group separately at post-treatment. The main outcome measure was the Liebowitz Social Anxiety Scale Self-Report.ResultsAt long-term follow-up, there was no effect of any genotype, or gene × gene interactions, on treatment response. In the subsamples, there was time by genotype interaction effects indicating an influence of the TPH2 G-703T-polymorphism on CBT short-term response, however the direction of the effect was not consistent across trials.ConclusionsNone of the three gene variants, 5-HTTLPR, COMTval158met and TPH2 G-703T, was associated with long-term response to CBT for SAD.
|
|
| 2. |
- Bornscheuer, Lisa, 1990-, et al.
(författare)
-
Functional Variation in the FAAH Gene Is Directly Associated with Subjective Well-Being and Indirectly Associated with Problematic Alcohol Use
- 2023
-
Ingår i: Genes. - 2073-4425. ; 14:9
-
Tidskriftsartikel (refereegranskat)abstract
- Fatty acid amide hydrolase (FAAH) is an enzyme that degrades anandamide, an endocannabinoid that modulates mesolimbic dopamine release and, consequently, influences states of well-being. Despite these known interactions, the specific role of FAAH in subjective well-being remains underexplored. Since well-being is a dynamic trait that can fluctuate over time, we hypothesized that we could provide deeper insights into the link between FAAH and well-being using longitudinal data. To this end, we analyzed well-being data collected three years apart using the WHO (Ten) Well-Being Index and genotyped a functional polymorphism in the FAAH gene (rs324420, Pro129Thr) in a sample of 2822 individuals. We found that the A-allele of rs324420, which results in reduced FAAH activity and elevated anandamide levels, was associated with lower well-being scores at both time points (Wave I, B: −0.52, p = 0.007; Wave II, B: −0.41, p = 0.03, adjusted for age and sex). A subsequent phenome-wide association study (PheWAS) affirmed our well-being findings in the UK Biobank (N = 126,132, alternative C-allele associated with elevated happiness, p = 0.008) and revealed an additional association with alcohol dependence. In our cohort, using lagged longitudinal mediation analyses, we uncovered evidence of an indirect association between rs324420 and problematic alcohol use (AUDIT-P) through the pathway of lower well-being (indirect effect Boot: 0.015, 95% CI [0.003, 0.030], adjusted for AUDIT in Wave I). We propose that chronically elevated anandamide levels might influence disruptions in the endocannabinoid system—a biological contributor to well-being—which could, in turn, contribute to increased alcohol intake, though multiple factors may be at play. Further genetic studies and mediation analyses are needed to validate and extend these findings.
|
|
| 3. |
- Bornscheuer, Lisa, et al.
(författare)
-
The cannabinoid receptor-1 gene interacts with stressful life events to increase the risk for problematic alcohol use
- 2022
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12
-
Tidskriftsartikel (refereegranskat)abstract
- Problematic alcohol use is a major contributor to the global burden of death and disabilities, and it represents a public health concern that has grown substantially following the COVID-19 pandemic. The available treatment options remain limited and to develop better pharmacotherapies for alcohol misuse we need to identify suitable biological targets. Previous research has implicated the brain’s endocannabinoid system (ECS) in psychiatric and stress-related outcomes, including substance use and habituation to repeated stress. Moreover, genetic variants in the cannabinoid-1 receptor gene (CNR1; CB1R) have been associated with personality traits, which are in turn predictors of substance use disorders. To date, however, no human genome-wide association study has provided evidence for an involvement of the ECS in substance use outcomes. One reason for this ECS-related “missing heritability” may be unexamined gene-environment interactions. To explore this possibility, we conducted cross-sectional analyses using DNA samples and stress-exposure data from a longitudinal Swedish population-based study (N = 2,915). Specifically, we genotyped rs2023239, a functional C/T single nucleotide polymorphism in CNR1, previously reported to be associated with CNR1 binding in the brain, subjective reward following alcohol intake, and alcohol cue-elicited brain activation. Our two outcomes of interest were (i) problematic alcohol use based on the Alcohol Use Disorders Identification Test (AUDIT), and (ii) personality trait scores based on the Five Factor Model. We found no baseline association between rs2023239 and problematic alcohol use or personality traits. However, there was a clear trend for interaction between rs2023239’s risk allele (C) and stressful life events (SLEs) in both childhood and adulthood, which predicted problematic alcohol use. Although not significant, there was also some indication that the risk allele interacted with child SLEs to increase scores on neuroticism. Our study supports the notion that the ECS can affect alcohol intake behaviors by interacting with life adversities and is—to the best of our knowledge—the first to focus on the interaction between CNR1 and stressors in both childhood and adulthood in humans. Further studies are warranted to confirm these findings.
|
|
| 4. |
- Galanti, Maria Rosaria, et al.
(författare)
-
School environment and mental health in early adolescence - a longitudinal study in Sweden (KUPOL)
- 2016
-
Ingår i: BMC Psychiatry. - : Springer Science and Business Media LLC. - 1471-244X. ; 16
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Longitudinal studies indicate strong associations between school proficiency and indicators of mental health throughout adulthood, but the mechanisms of such associations are not fully elucidated. The Kupol study is a prospective cohort study in Sweden set up in order to: (i) describe the association of school pedagogic and social environment and its specific dimensions with the risk of mental ill-health and psychiatric disorders in adolescence; (ii) evaluate the direct effects of school pedagogic and social environment on mental health and the effects mediated by the individual's academic achievements; and (iii) assess if school pedagogic and social environment are associated with mental ill-health through epigenetic mechanisms, in particular those involving genes regulating the response to stress.Methods: The Kupol cohort at baseline consists of 3959 children attending the 7th grade of compulsory school (13-14 years old) in 8 regions of central Sweden in the school years 2013-2014 or 2014-2015. Three follow-up surveys in subsequent years are planned. Teachers' and students' perceptions of the culture, climate and ethos of their schools, and students' mental ill-health are assessed at the whole school level by annual questionnaire surveys. In order to conduct epigenetic analyses saliva specimens are collected from a nested sample of students at inception and two years later. Further, class-, family-and child-level information is collected at baseline and during each year of follow-up. Self-reported information is being complemented with register data via record-linkages to national and regional health and administrative registers.Discussion: The topic being investigated is new, and the sample constitutes the largest adolescent cohort in Sweden involved in an ad hoc study. Epigenetic analyses centered on environmental cues to stress response are a thoroughly new approach. Finally a notable feature is the multi-informant and multi-method data collection, with surveys at the school, class, family, and student level. Collaboration and data access: interested investigators should contact the coordinating centre. Additional information is available on the study's website, http://kupolstudien.se/.
|
|
| 5. |
- Liu, Bojing, et al.
(författare)
-
Working conditions, serotonin transporter gene polymorphism (5-HTTLPR) and anxiety disorders : a prospective cohort study
- 2013
-
Ingår i: Journal of Affective Disorders. - : Elsevier BV. - 0165-0327 .- 1573-2517. ; 151:2, s. 652-659
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The etiology and pathology of anxiety disorders involve both genetic and environmental influences. Adverse working conditions may contribute to the development of anxiety. The serotonin transporter-linked polymorphic region (5-HTTLPR) has been implicated in stress sensitivity. Therefore, we investigated the potential interplay between 5-HTTLPR and job-related risk factors in the prediction of the occurrence of anxiety.METHODS: We conducted a prospective study using the first two waves of a Swedish population-based cohort. At Wave I, 1585 individuals without anxiety, depression or dysthymia who were active in the labor market during both waves were included. Information on job demands, skill discretion, decision authority and social climate was collected at Wave I. After a three year interval, the presence of anxiety disorders was determined at Wave II. All 1585 participants were genotyped for 5-HTTLPR. Both additive and multiplicative models were considered in examining the potential interaction between 5-HTTLPR and adverse working conditions on the development of anxiety.RESULTS: Anxiety was associated with high job demands but not with 5-HTTLPR. An interaction was observed between 5-HTTLPR and high job demands among females. Individuals with 5-HTTLPR high expression genotype (LL) developed anxiety disorders more frequently when exposed to high job demands compared to 'LS/SS' carriers.LIMITATIONS: A limited number of participants developed anxiety.CONCLUSIONS: High job demands predict the development of anxiety. The 5-HTT polymorphism has a moderating effect on the relationship between high job demands and anxiety among females.
|
|
| 6. |
- Melas, Philippe A., et al.
(författare)
-
Neuropeptide Y : Identification of a novel rat mRNA splice-variant that is downregulated in the hippocampus and the prefrontal cortex of a depression-like model
- 2012
-
Ingår i: Peptides. - : Elsevier BV. - 0196-9781 .- 1873-5169. ; 35:1, s. 49-55
-
Tidskriftsartikel (refereegranskat)abstract
- Neuropeptide Y (NPY) is known to influence emotional processing and decreased NPY levels have been associated with mood and anxiety disorders. Alternative splicing of pre-messenger RNA is a cellular mechanism that allows for transcriptome diversity, yet there is limited knowledge in this respect with regard to Npy. Since the hippocampus and the prefrontal cortex play an important role in affective disorders, we investigated alternative splicing of Npy in these regions of a rat model of depression (Flinders Sensitive Line, FSL) and its controls (Flinders Resistant Line, FRL). The existence of different Npy messenger RNA (mRNA) variants was examined using 5' and 3' RACE. In addition to the Npy mRNA species annotated in GenBank and Ensembl, we identified a novel short mRNA splice variant. Immunoblotting results argued against a putative translation of this short mRNA into protein in brain tissue. Compared to the FRL, the FSL had reduced short Npy mRNA levels in the HIP (P = 0.00014) and the PFC (P = 0.016). Gene expression analyses in five brain regions of an outbred rat strain supported the presence of the short Npy transcript in all examined regions and showed that it is expressed in similar to 2.4-fold lower levels than the long Npy mRNA. Finally, sequencing of the 5' RACE products revealed a transcription start site of Npy that is different from the currently annotated position. These data add to the characterization of the rat Npy mRNA and demonstrate the presence of a novel transcript with a so far unknown function.
|
|
| 7. |
- Månsson, Kristoffer, et al.
(författare)
-
Brain Signal Variability and Indices of Cellular Protection Predicts Social Anxiety Disorder Treatment Outcome
- 2019
-
Ingår i: Proceedings of the 9th World Congress of Behavioural & Cognitive Therapies. - Tübingen : dgvt-Verlag. - 9783871598517 ; , s. 158-158
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- We are currently lacking clinically useful predictors of treatment response in common psychiatric disorders. Non-invasive and increasingly accessible neuroimaging techniques like functional magnetic resonance imaging (fMRI) could be a useful tool. In contrast to the conventional approach investigating the brain’s average responses, the brain’s signal variability could be a better estimate of the brain’s dynamic operations (Garrett et al., 2010, 2015). In addition, telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, we investigate if baseline BOLD-fMRI signal variability, and indices of cellular protection, predicts social anxiety disorder patient’s response to internet-delivered cognitive behavior therapy. Forty-six patients with social anxiety disorder (SAD) were scanned twice with a 3 Tesla fMRI before initiating CBT. Treatment outcome was assessed the Liebowitz Social Anxiety Scale (self-report). 1) BOLD-fMRI acquisition was performed while passively viewing emotional faces flashing on the screen for 80 seconds. Raw BOLD-fMRI data was implemented in an Independent Component Analysis in order to manually denoise images by carefully remove noise from neural signal. Across time, each voxel’s standard deviation was calculated and used as an index of variability. Multivariate partial least squares regression models were used for second level analysis. 2) Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. Significant latent level brain scores, and baseline analytes were implemented in linear regressions with LSAS-SR change score as the outcome. Results will be presented and discussed.
|
|
| 8. |
- Månsson, Kristoffer, et al.
(författare)
-
Can Psychological Treatment Slow Down Cellular Aging in Social Anxiety Disorder? : An Intervention Study Evaluating Changes in Telomere Length and Telomerase Activity
- 2018
-
Ingår i: Biological Psychiatry. - : Elsevier BV. - 0006-3223 .- 1873-2402. ; 83:9, s. S351-S352
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Mental illness, including anxiety disorders, is linked to accelerated cell aging. This is evidenced by shorter leukocyte telomere length. Cells with critically short telomeres may undergo apoptosis. In dividing cells, telomere shortening is counteracted by the telomeraseenzyme. Telomerase is reportedly low following chronic psychological stress. We hypothesized that a psychological treatment may increase telomerase activity, less telomere attritionand greater symptom improvement.Methods: Forty-six patients (91% SSRI naïve) with social anxiety disorder(SAD; mean age 31, 63% females) underwent a 9-week waiting period, and 9 weeks of Internet-delivered cognitive behavior therapy(CBT). During treatment, symptoms were assessed weekly using the Liebowitz Social Anxiety Scale (LSAS-SR). Fasting blood samples were collected twice before treatment, and at post-treatment. Genomic DNA was extracted using DNeasy® Blood & Tissue Kit (Qiagene) to assess leukocyte telomere length. Telomerase activity was detected by real-time telomeric repeat amplification protocol (RT-TRAP).Results: Patients improved significantly on the LSAS-SR (p<.001; Cohen’s d=1.5). Pre-post changes in telomerase and telomere length correlated positively (Pearson’s r=.31, p=.05). Reduced telomerase activity (<33th percentile) was associated with less improvement and increased activity (>66th percentile) with more improvement on the LSAS-SR (Z=-2.4, p=.02).Conclusions: We demonstrate, to our knowledge for the first time, that altered telomerase activity is associated with clinical response to a psychological treatment in a psychiatric population. The observed CBT effect on telomerase in patients with SAD is consistent with results from animal trials and a small previous study of antidepressants in humans. Thus, telomerase activation may play an important role in clinical recovery.
|
|
| 9. |
- Månsson, Kristoffer N. T., et al.
(författare)
-
Improvement in indices of cellular protection after psychological treatment for social anxiety disorder
- 2019
-
Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Telomere attrition is a hallmark of cellular aging and shorter telomeres have been reported in mood and anxiety disorders. Telomere shortening is counteracted by the enzyme telomerase and cellular protection is also provided by the antioxidant enzyme glutathione peroxidase (GPx). Here, telomerase, GPx, and telomeres were investigated in 46 social anxiety disorder (SAD) patients in a within-subject design with repeated measures before and after cognitive behavioral therapy. Treatment outcome was assessed by the Liebowitz Social Anxiety Scale (self-report), administered three times before treatment to control for time and regression artifacts, and posttreatment. Venipunctures were performed twice before treatment, separated by 9 weeks, and once posttreatment. Telomerase activity and telomere length were measured in peripheral blood mononuclear cells and GPx activity in plasma. All patients contributed with complete data. Results showed that social anxiety symptom severity was significantly reduced from pretreatment to posttreatment (Cohen’s d = 1.46). There were no significant alterations in telomeres or cellular protection markers before treatment onset. Telomere length and telomerase activity did not change significantly after treatment, but an increase in telomerase over treatment was associated with reduced social anxiety. Also, lower pretreatment telomerase activity predicted subsequent symptom improvement. GPx activity increased significantly during treatment, and increases were significantly associated with symptom improvement. The relationships between symptom improvement and putative protective enzymes remained significant also after controlling for body mass index, sex, duration of SAD, smoking, concurrent psychotropic medication, and the proportion of lymphocytes to monocytes. Thus, indices of cellular protection may be involved in the therapeutic mechanisms of psychological treatment for anxiety.
|
|
| 10. |
- Persson, Ninni, et al.
(författare)
-
Effects of DARPP-32 Genetic Variation on Prefrontal Cortex Volume and Episodic Memory Performance
- 2017
-
Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 11
-
Tidskriftsartikel (refereegranskat)abstract
- Despite evidence of a fundamental role of DARPP-32 in integrating dopamine and glutamate signaling, studies examining gene coding for DARPP-32 in relation to neural and behavioral cor-relates in humans are scarce. Post mortem findings evidence genotype specific expressions of DARPP-32 in the dorsal frontal lobes. We therefore investigated the effects of genomic variation in DARPP-32 coding on frontal lobe volumes and episodic memory. Volumetric data from the dorsolateral (DLPFC), and visual cortices (VC) were obtained from 61 younger and older adults (♀54%). The major homozygote G, T or A genotypes in single nucleotide polymorphisms (SNPs: rs879606; rs907094; rs3764352), at the DARPP-32 regulating PPP1R1B gene influenced frontal gray matter volume and episodic memory (EM). Homozygous carriers of allelic variants with lower DARPP-32 expression had overall larger prefrontal volumes, in addition to greater EM recall accuracy. The SNPs did not influence VC volume. The genetic effects on DLPFC were greater in younger adults, and selective to this group for EM. Our findings suggest that genomic variation maps on to individual differences in frontal brain volumes, and cognitive functions. Larger DLPFC volumes were also related to better EM performance, suggesting that gene-related differences in frontal gray matter may contribute to individual differences in EM. These results need further replication from experimental and longitudinal reports to determine directions of causality.
|
|
