| 1. |
- Culverhouse, R. C., et al.
(författare)
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Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression
- 2018
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Ingår i: Molecular Psychiatry. - : Springer Science and Business Media LLC. - 1359-4184 .- 1476-5578. ; 23:1, s. 133-142
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Tidskriftsartikel (refereegranskat)abstract
- The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 data sets containing 38 802 European ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analysed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis) with qualifying unpublished data, were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalisable, but must be of modest effect size and only observable in limited situations.
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| 2. |
- Hodgins, Sheilagh, et al.
(författare)
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A 5-year follow-up study of adolescents who sought treatment for substance misuse in Sweden
- 2014
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Ingår i: European Child and Adolescent Psychiatry. - : Springer Science and Business Media LLC. - 1018-8827 .- 1435-165X. ; 23:5, s. 347-360
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that substance misuse in adolescence is associated with increased risks of hospitalizations for mental and physical disorders, convictions for crimes, poverty, and premature death from age 21 to 50. The present study examined 180 adolescent boys and girls who sought treatment for substance misuse in Sweden. The adolescents and their parents were assessed independently when the adolescents first contacted the clinic to diagnose mental disorders and collect information on maltreatment and antisocial behavior. Official criminal files were obtained. Five years later, 147 of the ex-clients again completed similar assessments. The objectives were (1) to document the prevalence of alcohol use disorders (AUD) and drug use disorders (DUD) in early adulthood; and (2) to identify family and individual factors measured in adolescence that predicted these disorders, after taking account of AUD and DUD in adolescence and treatment. Results showed that AUD, DUD, and AUD + DUD present in mid-adolescence were in most cases also present in early adulthood. Prediction models detected no positive effect of treatment in limiting persistence of these disorders. Thus, treatment-as-usual provided by the only psychiatric service for adolescents with substance misuse in a large urban center in Sweden failed to prevent the persistence of substance misuse. Despite extensive clinical assessments of the ex-clients and their parents, few factors assessed in mid-adolescence were associated with substance misuse disorders 5 years later. It may be that family and individual factors in early life promote the mental disorders that precede adolescent substance misuse.
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| 3. |
- Isaksson, Johan, et al.
(författare)
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Associations between the FKBP5 haplotype, exposure to violence and anxiety in females
- 2016
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Ingår i: Psychoneuroendocrinology. - Oxford, United Kingdom : Elsevier. - 0306-4530 .- 1873-3360. ; 72, s. 196-204
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Tidskriftsartikel (refereegranskat)abstract
- The gene that encodes the FK506-binding protein 5 (FKBP5) is regarded as a candidate for investigating how negative life events interact with a genetic predisposition to stress-related disorders, such as depression and anxiety. Given the role of FKBP5 as an important regulator of stress responses, we aimed to investigate if single-nucleotide polymorphisms (SNPs) in FKBP5-in the presence/absence of exposure to violence-are associated with symptoms of depression and anxiety. Data from two community-based samples of adolescents (n=1705) and young adults (n=1800) regarding ratings on depression, anxiety, exposure to violence and FKBP5 genotype were collected. A risk haplogenotype including the minor alleles of seven common SNPs in the FKBP5 (rs3800373, rs9296158, rs7748266, rs1360780, rs9394309, rs9470080 and rs4713916) conferred higher ratings on anxiety among females, but not males, in the presence of violence. Exposure to violence and female sex were associated with higher ratings on both depression and anxiety, with the exception of ratings on depression among young adults, on which sex had no effect. Ratings on depression were not associated with the haplogenotype. These findings may correspond to differences in the regulation of the HPA axis and with the higher vulnerability to anxiety in females.
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| 4. |
- Isaksson, Johan, et al.
(författare)
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Polymorphisms in the FK506 binding protein 5 gene are associated with attention deficit hyperactivity disorder and diurnal cortisol levels
- 2015
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Ingår i: Acta Paediatrica. - : WILEY. - 0803-5253 .- 1651-2227. ; 104:9, s. 910-915
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Tidskriftsartikel (refereegranskat)abstract
- AimPrevious studies have shown an association between childhood attention deficit hyperactivity disorder (ADHD) and a down-regulated hypothalamus-pituitary-adrenal axis (HPA axis) with low diurnal cortisol levels. Given the role of the FK506 binding protein 5 (FKBP5) as an important regulator of the negative feedback system of the HPA axis, we set out to investigate possible associations between single nucleotide polymorphisms (SNPs) in FKBP5 in relation to ADHD and diurnal cortisol levels. MethodsChildren with ADHD (n=81) and healthy comparisons (n=88) collected saliva four times during a regular school day for radioimmunoassay analysis of cortisol and for genotyping of five SNPs in FKBP5 (rs9296158, rs1360780, rs9470080, rs7748266 and rs9394309). ResultsWe found associations between SNP genotypes and ADHD as well as between genotypes and diurnal cortisol levels. One of these SNPs, rs9470080, was significantly associated with both ADHD and lower cortisol levels. ConclusionThis study contributes to previous findings on a down-regulated HPA axis in children with ADHD by demonstrating an association between ADHD, lower cortisol levels and SNPs of the FKBP5-gene. The relevance of these findings for the development and shaping of ADHD symptoms needs to be approached in larger samples, preferably also taking stress reactivity into consideration.
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| 5. |
- Isaksson, Johan, et al.
(författare)
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The Pressure-Activation-Stress scale in relation to ADHD and cortisol
- 2015
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Ingår i: European Child and Adolescent Psychiatry. - : Springer Science and Business Media LLC. - 1018-8827 .- 1435-165X. ; 24:2, s. 153-161
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Tidskriftsartikel (refereegranskat)abstract
- The Pressure-Activation-Stress (PAS) scale is a self-report questionnaire for children concerning perceived stress. To explore behavioral and physiological correlates, we investigated if scores discriminate between a group prone to perceive high levels of stress [children with attention-deficit/hyperactivity disorder (ADHD)] and a healthy school sample, and if they are associated with diurnal cortisol levels. The PAS scale was filled in at home by children (11-17 years) with clinically confirmed ADHD (n = 102) and non-affected comparisons (n = 146). Saliva samples were collected four times during a regular school day for radioimmunoassay analysis of cortisol. Subtypes and severity of ADHD symptoms were determined using parental rating scales. Children with ADHD scored higher on the PAS scale than a school sample. The PAS scores were similar over ages in the ADHD group while they increased with age in the healthy group. Female sex was associated with higher stress in both groups but no gender interaction was found. No association was found between PAS scores and cortisol levels in neither group. Children in the ADHD group had a lower ratio of cortisol levels/perceived stress on all sampling occasions, built up both by the higher PAS scores and the lower cortisol levels in children with ADHD. The higher PAS scores in children with ADHD support the validity of the scale. The lack of association between PAS scores and diurnal cortisol levels is intriguing and illustrates the complexity of the stress concept. Stress-related fragility seems to accompany ADHD during childhood.
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| 6. |
- Isaksson, Johan, et al.
(författare)
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Early psychosocial adversity and cortisol levels in children with attention-deficit/hyperactivity disorder
- 2013
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Ingår i: European Child and Adolescent Psychiatry. - : Springer Science and Business Media LLC. - 1018-8827 .- 1435-165X. ; 22:7, s. 425-432
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies suggest a different regulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) with lower diurnal cortisol levels, especially in the morning, in children with attention-deficit/hyperactivity disorder (ADHD) compared with controls. Since exposure to foetal and childhood psychosocial adversity has been associated with both ADHD and HPA-axis functioning, such exposures may explain these low cortisol levels in ADHD via early programming of the HPA-axis. Thus, our main aim was to retrospectively study foetal and early childhood exposures to psychosocial adversity in children with ADHD and to relate these exposures to cortisol levels. Saliva samples were collected during a regular weekday in children, 6-17 years old, with clinically confirmed ADHD (n = 197) and non-affected comparisons (n = 221) for radioimmunoassay analysis of cortisol. Parental rating scales were used for categorising subtypes of ADHD and degree of exposure to adversity. Children with ADHD had more reports of at least one rated foetal adversity (p = 0.041) and childhood adversity (p < 0.001) than comparisons. The association between low morning cortisol levels and ADHD-symptoms remained when analyses were adjusted for adversities, age, sex, sampling time and symptoms of oppositional defiant disorder. No relation was found between exposures to foetal/childhood adversity and cortisol levels except for a positive relation between childhood adversity and cortisol morning increase in children with ADHD. The hypothesis that early adversity may influence the HPA-axis, leading to lower cortisol levels in children with ADHD, was not supported by our findings.
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| 7. |
- Bendre, Megha, et al.
(författare)
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Associations Between MAOA-uVNTR Genotype, Maltreatment, MAOA Methylation, and Alcohol Consumption in Young Adult Males
- 2018
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Ingår i: Alcoholism. - : WILEY. - 0145-6008 .- 1530-0277. ; 42:3, s. 508-519
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundEpigenetic mechanisms are candidate moderators of the effect of maltreatment on brain and behavior. Interactions between maltreatment and the monoamine oxidase A upstream variable number tandem repeat genotype (MAOA-uVNTR) are associated with alcohol-related problems. However, presently it is not known whether DNA methylation moderates this association. The study focused on 53 young adult males and aimed to determine whether MAOA methylation moderated the association of alcohol-related problems with the interaction of MAOA-uVNTR and maltreatment, and whether alcohol consumption moderated the association of MAOA methylation with the interaction of MAOA-uVNTR and maltreatment. MethodsMAOA-uVNTR genotypes with 3 and > 3 repeats were categorized as short (S) and long (L), respectively. Data on maltreatment were obtained retrospectively, using self-reported questionnaires. DNA methylation of 16 candidate CpGs within part of the MAOA first exon and intron was assessed and grouped based on principal component analyses. Alcohol-related problems were assessed using the Alcohol Use Disorders Identification Test (AUDIT). Alcohol consumption was measured using AUDIT-C. Moderation effects were assessed and probed using the moderated moderation model and Johnson-Neyman's method, respectively. ResultsCarriers of the S allele, who experienced maltreatment and displayed lower Component 1 (mean of CpGs 13-16 in the first intron) MAOA methylation levels, reported higher AUDIT score in contrast to L-allele carriers. Carriers of the S allele, who reported higher AUDIT-C score and experienced maltreatment, displayed lower Component 3 (mean of CpGs 2-6 in the first exon) MAOA methylation levels than L-allele carriers. ConclusionsIntronic methylation moderated the association of alcohol-related problems with the interaction of MAOA-uVNTR and maltreatment. Alcohol consumption moderated the association of exonic methylation with the interaction of MAOA-uVNTR and maltreatment. These results suggest that epigenetic factors as well as genotype and maltreatment play a role in the development of alcohol misuse among young adult males.
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| 8. |
- Bendre, Megha, et al.
(författare)
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Early life stress and voluntary alcohol consumption in relation to Maoa methylation in male rats.
- 2019
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Ingår i: Alcohol. - : Elsevier BV. - 0741-8329 .- 1873-6823. ; 79, s. 7-16
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Tidskriftsartikel (refereegranskat)abstract
- Early life stress (ELS) or alcohol consumption can influence DNA methylation and affect gene expression. The monoamine oxidase A (Maoa) encodes the enzyme that metabolizes monoaminergic neurotransmitters crucial for the stress response, alcohol reward, and reinforcement. Previously, we reported lower Maoa expression in the nucleus accumbens and dorsal striatum of male rats exposed to ELS during the first three postnatal weeks, and to voluntary alcohol consumption in adulthood, compared with controls. The present study continued to investigate the effect of ELS and alcohol consumption on Maoa methylation, and its relation to Maoa expression in these animals. We selected candidate CpGs after performing next-generation bisulfite sequencing of the Maoa promoter, intron 1-5, exons 5 and 6, together comprised of 107 CpGs, in a subgroup of rats. Pyrosequencing was used to analyse the methylation of ten candidate CpGs in the promoter and intron 1 in the entire sample. ELS and alcohol displayed an interaction effect on CpG-specific methylation in the dorsal striatum. CpG-specific methylation correlated with Maoa expression, corticosterone levels, and alcohol consumption in a brain region-specific manner. CpG-specific methylation in the Maoa promoter was a potential moderator of the interaction of ELS with alcohol consumption on Maoa expression in the NAc. However, the findings were sparse, did not survive correction for multiple testing, and the magnitude of differences in methylation levels was small. In conclusion, CpG-specific Maoa methylation in the promoter and intron 1 may associate with ELS, alcohol consumption and Maoa expression in reward-related brain regions.
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| 9. |
- Bendre, Megha, et al.
(författare)
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Effect of voluntary alcohol consumption on Maoa expression in the mesocorticolimbic brain of adult male rats previously exposed to prolonged maternal separation. : Maoa,ELS and alcohol
- 2015
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Ingår i: Translational Psychiatry. - : Springer Science and Business Media LLC. - 2158-3188. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Discordant associations between monoamine oxidase A (MAOA) genotype and high alcohol drinking have been reported in human and non-human primates. Environmental influences likely moderate genetic susceptibility. The biological basis for this interplay remains elusive, and inconsistencies call for translational studies in which conditions can be controlled and brain tissue is accessible. The present study investigated whether early life stress and subsequent adult episodic alcohol consumption affect Maoa expression in stress- and reward-related brain regions in the rat. Outbred Wistar rats were exposed to rearing conditions associated with stress (prolonged maternal separation) or no stress during early life, and given free choice between alcohol and/or water in adulthood. Transcript levels of Maoa were assessed in the ventral tegmental area, nucleus accumbens (NAc), medial prefrontal cortex, cingulate cortex, amygdala and dorsal striatum (DS). Blood was collected to assess corticosterone levels. After alcohol consumption, lower blood corticosterone and Maoa expression in the NAc and DS were found in rats exposed to early life stress compared with control rats. An interaction between early life stress and voluntary alcohol intake was found in the NAc. Alcohol intake before death correlated negatively with Maoa expression in DS in high alcohol-drinking rats exposed to early life stress. Maoa expression is sensitive to adulthood voluntary alcohol consumption in the presence of early life stress in outbred rats. These findings add knowledge of the molecular basis of the previously reported associations between early life stress, MAOA and susceptibility to alcohol misuse.
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| 10. |
- Checknita, David, et al.
(författare)
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Associations of monoamine oxidase A gene first exon methylation with sexual abuse and current depression in women
- 2018
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Ingår i: Journal of neural transmission. - : SPRINGER WIEN. - 0300-9564 .- 1435-1463. ; 125:7, s. 1053-1064
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Tidskriftsartikel (refereegranskat)abstract
- Childhood physical abuse (PA) and sexual abuse (SA) interact with monoamine oxidase A (MAOA) gene polymorphism to modify risk for mental disorders. In addition, PA and SA may alter gene activity through epigenetic mechanisms such as DNA methylation, thereby further modifying risk for disorders. We investigated whether methylation in a region spanning the MAOA first exon and part of the first intron was associated with PA and/or SA, MAOA genotype, alcohol dependence, drug dependence, depression disorders, anxiety disorders, and conduct disorder. 114 Swedish women completed standardized diagnostic interviews and questionnaires to report PA and SA, and provided saliva samples for DNA extraction. DNA was genotyped for MAOA-uVNTR polymorphisms, and methylation of a MAOA region of interest (chrX: 43,515,544-43,515,991) was measured. SA, not PA, was associated with hypermethylation of the MAOA first exon relative to no-abuse, and the association was robust to adjustment for psychoactive medication, alcohol and drug dependence, and current substance use. SA and MAOA-uVNTR genotype, but not their interaction, was associated with MAOA methylation. SA associated with all measured mental disorders. Hypermethylation of MAOA first exon mediated the association of SA with current depression, and both methylation levels and SA independently predicted lifetime depression. Much remains to be learned about the independent effects of SA and MAOA-uVNTR genotypes on methylation of the MAOA first exon.
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