Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.

BACKGROUND: Evidence from rodents indicated that after recent stress, reduced expression of tight junction protein claudin-5 may weaken the blood-brain barrier and allow interleukin-6 to induce depressive symptoms. Our aims were to prove this pathomechanism in humans. METHODS: We used a large population genetic database (UK Biobank, n = 277 501) to test whether variation in the CLDN5 gene could modulate effects of the IL6 gene variant in stress-induced depression. Three-way interaction of functional polymorphisms, rs885985 of CLDN5, and rs1800795 of IL6 with recent stressful life events were tested on current depressive symptoms. Analyses were performed in male and female populations as well. RESULTS: The 3-way interaction including recent stress yielded highly significant results on current depressive symptoms in the UK Biobank sample, which was more pronounced in men and could be replicated on trend level in an independent cohort (NewMood, n = 1638). None of any other associations or interactions, including, for example, childhood stressors and lifetime depression as an outcome, yielded significance. CONCLUSIONS: These findings provide genetic evidence in humans for the interaction among interleukin-6, claudin-5, and recent stress, suggesting that inflammation is involved in the development of depression and that stress-connected brain entry of inflammatory molecules is a key factor in this pathomechanism. These genetic polymorphisms may help to identify people at higher risk for recent stress-induced depression.

Childhood Adversity Moderates the Effects of HTR2A Epigenetic Regulatory Polymorphisms on Rumination.

The serotonin system has been suggested to moderate the association between childhood maltreatment and rumination, with the latter in its turn reported to be a mediator in the depressogenic effect of childhood maltreatment. Therefore, we investigated whether the associations of two epigenetic regulatory polymorphisms in the HTR2A serotonin receptor gene with Ruminative Responses Scale rumination and its two subtypes, brooding and reflection, are moderated by childhood adversity (derived from the Childhood Trauma Questionnaire) among 1,501 European white adults. We tested post hoc whether the significant associations are due to depression. We also tested the replicability of the significant results within the two subsamples of Budapest and Manchester. We revealed two significant models: both the association of methylation site rs6311 with rumination and that of miRNA binding site rs3125 (supposed to bind miR-1270, miR-1304, miR-202, miR-539 and miR-620) with brooding were a function of childhood adversity, and both interaction findings were significantly present both in the never-depressed and in the ever-depressed group. Moreover, the association of rs3125 with brooding could be replicated across the separate subsamples, and remained significant even when controlling for lifetime depression and the Brief Symptom Inventory depression score. These findings indicate the crucial importance of involving stress factors when considering endophenotypes and suggest that brooding is a more promising endophenotype than a broader measure of rumination. Transdiagnostic relevance of the brooding endophenotype and the potential of targeting epigenetic regulatory polymorphisms of HTR2A in primary and secondary prevention of depression and possibly of other disorders are also discussed.

Significance of risk polymorphisms for depression depends on stress exposure.

Depression is a polygenic and multifactorial disorder where environmental effects exert a significant impact, yet most genetic studies do not consider the effect of stressors which may be one reason for the lack of replicable results in candidate gene studies, GWAS and between human studies and animal models. Relevance of functional polymorphisms in seven candidate genes previously implicated in animal and human studies on a depression-related phenotype given various recent stress exposure levels was assessed with Bayesian relevance analysis in 1682 subjects. This Bayesian analysis indicated a gene-environment interaction whose significance was also tested with a traditional multivariate analysis using general linear models. The investigated genetic factors were only relevant in the moderate and/or high stress exposure groups. Rank order of genes was GALR2 > BDNF > P2RX7 > HTR1A > SLC6A4 > CB1 > HTR2A, with strong relevance for the first four. Robust gene-gene-environment interaction was found between BDNF and HTR1A. Gene-environment interaction effect was confirmed, namely no main effect of genes, but a significant modulatory effect on environment-induced development of depression were found. Our data support the strong causative role of the environment modified by genetic factors, similar to animal models. Gene-environment interactions point to epigenetic factors associated with risk SNPs. Galanin-2 receptor, BDNF and X-type purin-7 receptor could be drug targets for new antidepressants.

Rumination in migraine: Mediating effects of brooding and reflection between migraine and psychological distress.

OBJECTIVE: The relationship between migraine and psychological distress has been consistently reported in cross-sectional and longitudinal studies. We hypothesised that a stable tendency to perseverative thoughts such as rumination would mediate the relationship between migraine and psychological distress. Design and Main Outcomes Measures: Self-report questionnaires measuring depressive rumination, current psychological distress and migraine symptoms in two independent European population cohorts, recruited from Budapest (N = 1139) and Manchester (N = 2004), were used. Structural regression analysis within structural equation modelling was applied to test the mediational role of brooding and reflection, the components of rumination, between migraine and psychological distress. Sex, age and lifetime depression were controlled for in the analysis. RESULTS: Migraine predicted higher brooding and reflection scores, and brooding proved to be a mediator between migraine and psychological distress in both samples, while reflection mediated the relationship significantly only in the Budapest sample. CONCLUSIONS: Elevated psychological distress in migraine is partially attributed to ruminative response style. Further studies are needed to expand our findings to clinical samples and to examine how rumination links to the adjustment to migraine.

Variability in the effect of 5-HTTLPR on depression in a large European population: the role of age, symptom profile, type and intensity of life stressors.

BACKGROUND: Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity. METHODS: In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models. RESULTS: The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (≤30) individuals. LIMITATIONS: Our study is cross-sectional and applies self-report questionnaires. CONCLUSIONS: Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.

Brain galanin system genes interact with life stresses in depression-related phenotypes.

Galanin is a stress-inducible neuropeptide and cotransmitter in serotonin and norepinephrine neurons with a possible role in stress-related disorders. Here we report that variants in genes for galanin (GAL) and its receptors (GALR1, GALR2, GALR3), despite their disparate genomic loci, conferred increased risk of depression and anxiety in people who experienced childhood adversity or recent negative life events in a European white population cohort totaling 2,361 from Manchester, United Kingdom and Budapest, Hungary. Bayesian multivariate analysis revealed a greater relevance of galanin system genes in highly stressed subjects compared with subjects with moderate or low life stress. Using the same method, the effect of the galanin system genes was stronger than the effect of the well-studied 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4). Conventional multivariate analysis using general linear models demonstrated that interaction of galanin system genes with life stressors explained more variance (1.7%, P = 0.005) than the life stress-only model. This effect replicated in independent analysis of the Manchester and Budapest subpopulations, and in males and females. The results suggest that the galanin pathway plays an important role in the pathogenesis of depression in humans by increasing the vulnerability to early and recent psychosocial stress. Correcting abnormal galanin function in depression could prove to be a novel target for drug development. The findings further emphasize the importance of modeling environmental interaction in finding new genes for depression.

A comparison of permutation and parametric testing for between group effective connectivity differences using DCM.

Effective connectivity is becoming an increasingly popular technique for obtaining additional information from functional magnetic resonance imaging (fMRI) cognitive activation studies. It is potentially important for investigating psychiatric illnesses, which are thought to depend on disrupted connections and in observing the action of psychoactive drugs used to treat these disorders. If researchers are to apply these techniques confidently then it is important to establish the level of power that is available in an experiment. This study compares the level of power available when applying effective connectivity to test for differences between groups using parametric tests and permutation testing. Permutation testing has previously been shown to have superior sensitivity to parametric tests in fMRI studies. As an illustrative example, both the parametric t-test and equivalent permutation test were applied to a comparison between healthy controls and remitted depressed volunteers performing an emotional face processing task. Permutation testing was found to provide superior power compared with the nonparametric equivalent.

Quantitative frontal and temporal structural MRI studies in personality-disordered offenders and control subjects.

High rates of temporal and frontal lobe dysfunction have been reported in neuropsychological and EEG studies of incarcerated personality-disordered (PD) offenders, but there have been few quantitative structural magnetic resonance imaging (MRI) studies. We investigated whether impulsive-aggressive male PD patients showed evidence of reduced brain volumes in frontal and temporal brain regions on MRI compared with healthy control subjects. All subjects were screened for axis I pathology and brain abnormalities. Quantitative measures of frontal and temporal lobe volume were computed on MR images of the brain in 19 control subjects and 18 patients who did not show any evidence of brain pathology on diagnostic MRI scans. Temporal lobe volumes were 20% smaller in PD patients than control subjects, but the predicted reductions in frontal lobe volume did not occur, despite evidence of impairments in executive function. There was no evidence of differences in asymmetry of brain structures. The study further implicates temporal lobes in the pathogenesis of severe personality disorder, but does not support the notion that PDs characterised by impulsive-aggressive traits have abnormalities in brain symmetry similar to those reported in mentally ill populations. Higher-resolution MRI studies are needed to localise the abnormalities and to determine their nature.