Genetically reduced FAAH activity may be a risk for the development of anxiety and depression in persons with repetitive childhood trauma

Fatty acid amide hydrolase (FAAH) inhibitors are addressed for promising anxiolytics, but human studies on genetically reduced FAAH activity, stress and affective phenotypes are scarce. We investigated the effect of a functional polymorphism of FAAH (FAAH C385A or rs324420; low FAAH activity and high anandamide concentration are associated with the A allele) together with childhood adversity on the anxious and depressive phenotypes in 858 subjects from the general population. Phenotypes were measured by the Zung Self-Rating Depression Scale (ZSDS), the depression and anxiety subscales of the Brief Symptom Inventory (BSI-DEP, BSI-ANX) and the State-Trait Anxiety scales (STAI-S, STAI-T). Childhood Adversity Questionnaire (CHA) was used to assess early life traumas. Frequency of the A allele was greater among subjects with high ZSDS scores compared to the CC genotype. Furthermore, FAAH C385A and the CHA have shown a robust gene-environment interaction, namely, significantly higher anxiety and depression scores were exhibited by individuals carrying the A allele if they had high CHA scores compared to CC carriers. These data provided preliminary evidence that genetically reduced FAAH activity and repetitive stress in the childhood are associated with increased vulnerability for anxiety and depression in later life. Our results together with earlier experimental data suggest that permanently elevated anandamide level together with early life stress may cause a lifelong damage on stress response probably via the downregulation of CB1R during the neurodevelopment in the brain. It may also point to pharmacogenomic consequences, namely ineffectiveness or adverse effects of FAAH inhibitors in this subpopulation

Cultural differences in the development and characteristics of depression.

Depression is a highly prevalent mental illness with increasing burden for the patients, their families and society as well. In spite of its increasing importance, we still do not have complete understanding either of the phenomenology or the etiopathological background of depression, and cross-country, cross-ethnic and cross-cultural differences in the prevalence and symptomatic manifestation of depression further obscure this picture. Culturally-related features of depressive illness are gaining more importance in clinical practice with the increasing migration trends worldwide. In spite of the differences replicated in multiple studies, no exhaustive explanations are offered so far. In the present paper we describe the most consistently replicated findings concerning the most important cross-national differences in the rates and characteristics of depression with a short comment on possible background factors

Antidepressant treatment response is modulated by genetic and environmental factors and their interactions

Although there is a wide variety of antidepressants with different mechanisms of action available, the efficacy of treatment is not satisfactory. Genetic factors are presumed to play a role in differences in medication response; however, available evidence is controversial. Even genome-wide association studies failed to identify genes or regions which would consequently influence treatment response. We conducted a literature review in order to uncover possible mechanisms concealing the direct effects of genetic variants, focusing mainly on reports from large-scale studies including STAR*D or GENDEP. We observed that inclusion of environmental factors, gene-environment and gene-gene interactions in the model improves the probability of identifying genetic modulator effects of antidepressant response. It could be difficult to determine which allele of a polymorphism is the risk factor for poor treatment outcome because depending on the acting environmental factors different alleles could be advantageous to improve treatment response. Moreover, genetic variants tend to show better association with certain intermediate phenotypes linked to depression because these are more objective and detectable than traditional treatment outcomes. Thus, detailed modeling of environmental factors and their interactions with different genetic pathways could significantly improve our understanding of antidepressant efficacy. In addition, the complexity of depression itself demands a more comprehensive analysis of symptom trajectories if we are to extract useful information which could be used in the personalization of antidepressant treatment

Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression

Alterations in the folate pathway have been related to both major depression and cognitive inflexibility; however, they have not been investigated in the genetic background of ruminative response style, which is a form of perseverative cognition and a risk factor for depression. In the present study, we explored the association of rumination (measured by the Ruminative Responses Scale) with polymorphisms of two distinct folate pathway genes, MTHFR rs1801133 (C677T) and MTHFD1L rs11754661, in a combined European white sample from Budapest, Hungary (n=895) and Manchester, United Kingdom (n=1309). Post hoc analysis investigated whether the association could be replicated in each of the two samples, and the relationship between folate pathway genes, rumination, lifetime depression and Brief Symptom Inventory depression score. Despite its functional effect on folate metabolism, the MTHFR rs1801133 showed no effect on rumination. However, the A allele of MTHFD1L rs11754661 was significantly associated with greater rumination, and this effect was replicated in both the Budapest and Manchester samples. In addition, rumination completely mediated the effects of MTHFD1L rs11754661 on depression phenotypes. These findings suggest that the MTHFD1L gene, and thus the C1-THF synthase enzyme of the folate pathway localized in mitochondria, has an important effect on the pathophysiology of depression through rumination, and maybe via this cognitive intermediate phenotype on other mental and physical disorders. Further research should unravel whether the reversible metabolic effect of MTHFD1L is responsible for increased rumination or other long-term effects on brain development

Az endokannabinoid rendszer genetikai asszociációs vizsgálatai szorongással összefüggésben [Genetic association analyses of the endocannabinoid system on anxious phenotype]

BACKGROUND: Accumulating data confirmed that the endocannabinoid system (ECS) is involved in the regulation of stress response and emotional processes, therefore ECS became an important pharmacological target as a potential anxiolytic. Although unequivocal data from animal studies confirmed the relevancy of the ECS in anxious phenotype, human genetic data are poorly available in the literature in this field. In the presented studies we tested possible associations between anxious phenotype and the cannabinoid receptor 1 and the fatty acid amide hydrolase gene polymorphisms. METHODS: Almost 900 subjects were involved in our study from the general population. Anxious phenotype was measured by the State-Trait Anxiety Inventory (STAI) and the anxious subscale of the Brief Symptom Inventory (BSI-ANX). Genetic polymorphisms were genotyped from buccal mucosa samples' DNA by MassArray Sequenom technic. General linear models and post hoc tests were performed for statistical analyses. RESULTS: Phenotypic variances were not dependent on single marker's effect. However, interaction analyses provided significant results. Carriers of GG genotype of the rs2180619 scored significantly higher on the STAI-T scale in presence of SS genotype of 5-HTTLPR compared to other allelic variants (p=0.0006). SS genotype together with GG genotype meant almost a 5-fold risk to be anxious (OR=4.64, 95% CI: 1.7-12.71). In case of the C385A polymorphism of FAAH gene, A allele was associated with high scores of the BSI-ANX and the STAI-T if there were multiple childhood traumas in the anamnesis compared to C allele (pinteract=0.00002; pinteract=0.0023; respectively). CONCLUSION: Our results confirmed earlier positive data on the association between ECS and anxious phenotype. According to our findings ECS plays a significant role in the pathomechanism of anxious disorders by a complex mechanism of genetic interaction with the serotonin transporter gene and childhood traumas

Genetic variants in major depressive disorder: From pathophysiology to therapy

In spite of promising preclinical results there is a decreasing number of new registered medications in major depression. The main reason behind this fact is the lack of confirmation in clinical studies for the assumed, and in animals confirmed, therapeutic results. This suggests low predictive value of animal studies for central nervous system disorders. One solution for identifying new possible targets is the application of genetics and genomics, which may pinpoint new targets based on the effect of genetic variants in humans. The present review summarizes such research focusing on depression and its therapy. The inconsistency between most genetic studies in depression suggests, first of all, a significant role of environmental stress. Furthermore, effect of individual genes and polymorphisms is weak, therefore gene x gene interactions or complete biochemical pathways should be analyzed. Even genes encoding target proteins of currently used antidepressants remain non-significant in genome-wide case control investigations suggesting no main effect in depression, but rather an interaction with stress. The few significant genes in GWASs are related to neurogenesis, neuronal synapse, cell contact and DNA transcription and as being nonspecific for depression are difficult to harvest pharmacologically. Most candidate genes in replicable GxE interactions, on the other hand, are connected to the regulation of stress and the HPA axis and thus could serve as drug targets for a depression subgroups characterized by stress-sensitivity and anxiety while other risk polymorphisms such as those related to prominent cognitive symptoms in depression may help to identify additional subgroups and their distinct treatment. Until these new targets find their way in the therapy, the optimization of current medications can be approached by pharmacogenomics, where metabolizing enzyme polymorphisms remain prominent determinants of therapeutic success

Embers of the Past: Early Childhood Traumas Interact with Variation in P2RX7 Gene Implicated in Neuroinflammation on Markers of Current Suicide Risk

Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk

Genetic effects on educational attainment in Hungary

INTRODUCTION: Educational attainment is a substantially heritable trait, and it has recently been linked to specific genetic variants by genome‐wide association studies (GWASs). However, the effects of such genetic variants are expected to vary across environments, including countries and historical eras. METHODS: We used polygenic scores (PGSs) to assess molecular genetic effects on educational attainment in Hungary, a country in the Central Eastern European region where behavioral genetic studies are in general scarce and molecular genetic studies of educational attainment have not been previously published. RESULTS: We found that the PGS is significantly associated with the attainment of a college degree as well as the number of years in education in a sample of Hungarian study participants (N = 829). PGS effect sizes were not significantly different when compared to an English (N = 976) comparison sample with identical measurement protocols. In line with previous Estonian findings, we found higher PGS effect sizes in Hungarian, but not in English participants who attended higher education after the fall of Communism, although we lacked statistical power for this effect to reach significance. DISCUSSION: Our results provide evidence that polygenic scores for educational attainment have predictive value in culturally diverse European populations