Gene - maltreatment interplay in adult ADHD symptoms: main role of a gene-environment correlation effect in a Brazilian population longitudinal study.

Childhood maltreatment correlates with attention-deficit/hyperactivity disorder (ADHD) in previous research. The interaction between ADHD genetic predisposition and maltreatment's impact on ADHD symptom risk remains unclear. We aimed to elucidate this relationship by examining the interplay between a polygenic score for ADHD (ADHD-PGS) and childhood maltreatment in predicting ADHD symptoms during young adulthood. Using data from the 2004 Pelotas (Brazil) birth cohort comprising 4231 participants, we analyzed gene-environment interaction (GxE) and correlation (rGE). We further explored rGE mechanisms through mediation models. ADHD symptoms were assessed at age 18 via self-report (Adult Self Report Scale - ASRS) and mother-reports (Strength and Difficulties Questionnaire - SDQ). The ADHD-PGS was derived from published ADHD GWAS meta-analysis. Physical and psychological child maltreatment was gauged using the Parent-Child Conflict Tactics Scale (CTSPC) at ages 6 and 11, with a mean score utilized as a variable. The ADHD-PGS exhibited associations with ADHD symptoms on both ASRS (ß = 0.53; 95% CI: 0.03; 1.03, p = 0.036), and SDQ (ß = 0.20; 95% CI: 0.08; 0.32, p = 0.001) scales. The total mean maltreatment score was associated with ADHD symptoms using both scales [(ßASRS = 0.51; 95% CI: 0.26;0.77) and (ßSDQ = 0.24; 95% CI: 0.18;0.29)]. The ADHD-PGS was associated with total mean maltreatment scores (ß = 0.09; 95% CI: 0.01; 0.17; p = 0.030). Approximately 47% of the total effect of ADHD-PGS on maltreatment was mediated by ADHD symptoms at age 6. No evidence supported gene-environment interaction in predicting ADHD symptoms. Our findings underscore the significant roles of genetics and childhood maltreatment as predictors for ADHD symptoms in adulthood, while also indicating a potential evocative mechanism through gene-environment correlation.

Temperament traits mediate the relationship between CACNA1C polymorphisms and bipolar disorder in cisgender women.

The influence of temperament traits on bipolar disorder (BD) has been investigated. Both temperament traits and BD are partially genetically determined and seem to be influenced by variations in the CACNA1C gene. These variations presented a significant interactive effect with biological sex, although studies that evaluate this relationship are scarce. Here, we assessed the mediation effect of temperament traits on the relationship between two polymorphisms in the CACNA1C gene (rs1006737 and rs4765913) and BD according to sex. This is a cross-sectional study consisting of 878 Caucasian individuals (508 women and 370 men), aged 18-35, enrolled in a population-based study in the city of Pelotas, Southern Brazil. BD diagnosis was evaluated using the clinical interview MINI 5.0, and temperament traits were assessed via the application of the Affective and Emotional Composite Temperament Scale (AFECTS). Mediation models were tested using the modeling tool PROCESS (version 3.3) for SPSS. Bootstrapping-enhanced mediation analyses in women indicated that traits anger (39%) and caution (27%) mediated the association between the rs4765913 SNP and BD, while traits volition (29%), anger (35%), and caution (29%) mediated the association between the AA haplotype (rs1006737-rs4765913) and the BD. No effect was encountered for cisgender men. Our model revealed that paths from CACNA1C SNPs to BD are mediated by specific temperament traits in women, reinforcing the definition of temperament traits as endophenotypes.

BDNF Levels According to Variations in the CACNA1C Gene: Sex-Based Disparity.

The CACNA1C gene encodes the pore-forming alpha-1c subunit of L-type voltage-gated calcium channels. The calcium influx through these channels regulates the transcription of the brain-derived neurotrophic factor (BDNF). Polymorphisms in this gene have been consistently associated with psychiatric disorders, and alterations in BDNF levels are a possible biological mechanism to explain such associations. Here, we sought to investigate the effect of the CACNA1C rs1006737 and rs4765913 polymorphisms and their haplotypes on serum BDNF concentration. We further aim to investigate the regulatory function of these SNPs and the ones linked to them. The study enrolled 641 young adults (362 women and 279 men) in a cross-sectional population-based survey. Linear regression was used to test the effects of polymorphisms and haplotypes on BDNF levels adjusted for potential confounders. Moreover, regulatory putative functional roles were assessed using in silico approach. BDNF levels were not associated with CACNA1C polymorphisms/haplotype in the total sample. When the sample was stratified by sex, checking the effect of polymorphisms on men and women separately, the A-allele of rs4765913 was associated with lower BDNF levels in women compared with the TT genotype (p = 0.010). The AA (rs1006737-rs4765913) haplotype was associated with BDNF levels in opposite directions regarding sex, with lower levels of BDNF in women (p = 0.040) compared to those without this haplotype, while with higher levels in men (p = 0.027). These findings were supported by the presence of regulatory marks only on the male fetal brain. Our results suggest that the BDNF levels regulation may be a potential mechanism underpinning the association between CACNA1C and psychiatric disorders, with a differential role in women and men.

Genetic Variations in Elements of the Oxytocinergic Pathway are Associated with Attention/Hyperactivity Problems and Anxiety Problems in Childhood.

Genetic alterations related to oxytocin system seem to influence the neurobiology of attention-deficit hyperactivity disorder and anxiety problems leading to greater functional, social and emotional impairment. Here, we analyzed the association of OXTR rs2254298 and CD38 rs6449182 variants with attention/hyperactivity problems and anxiety problems in children. The study enrolled 292 children and adjusted regression model revealed OXTR rs2254298 AA genotype as a risk factor for attention deficit/hyperactivity problems (PR: 2.37; PadjFDR = 0.006), attention problems (PR: 2.71; PadjFDR = 0.003) and anxiety problems (PR: 1.92; PadjFDR = 0.018). CD38 rs6449182 G allele showed as a risk factor for attention deficit/hyperactivity problems (PR: 1.56; PadjFDR = 0.028). Moreover, in silico approach for regulatory roles found markers that influence chromatin accessibility and transcription capacity. Together, these data provide genetic information of oxytocin in developmental and behavioral disorders opening a range of opportunities for future studies that clarify their neurobiology in childhood.

Interaction between COMT Val158 Met polymorphism and childhood trauma predicts risk for depression in men.

Depression is a disabling illness with complex etiology. While the catechol-O-methyltransferase (COMT) gene, in particular the functional Val158 Met polymorphism, has been related to depression, the mechanisms underlying this gene-disease association are not completely understood. Therefore, we explore the association of COMT Val158 Met polymorphism with depression as well as its interaction with childhood trauma in 1136 young adults from a population-based study carried out in the city of Pelotas, Brazil. The diagnosis was performed through the Mini International Neuropsychiatric Interview 5.0 (MINI 5.0), and trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Total DNA was extracted and genotyped by real-time PCR, and the QTLbase dataset was queried to perform large-scale quantitative trait locus (QTL) analysis. Our research showed no direct association between the Val158 Met polymorphism and the diagnosis of depression (women: χ2  = 0.10, d = 1, p = 0.751; men: χ2  = 0.003, df = 1, p = 0.956). However, the Met-allele of the Val158 Met polymorphism modified the effect of childhood trauma in men (OR = 2.58 [95% CI: 1.05-6.29]; p = 0.038) conferring risk for depression only on those who suffer from trauma. The conditional effect from moderation analysis showed that trauma impacts the risk of depression only in men carrying the Met-allele (effect: 0.9490, standard error [SE]: 0.2570; p = 0.0002). QTLbase and dataset for Val158 Met polymorphism were consistent for markers that influence chromatin accessibility transcription capacity including histone methylation and acetylation. The changes caused in gene regulation by childhood trauma exposure and polymorphism may serve as evidence of the mechanism whereby the interaction increases susceptibility to this disorder in men.

Antimicrobial and cytotoxic capacity of pyroligneous extracts films of Eucalyptus grandis and chitosan for oral applications.

Chitosan films containing distilled pyroligneous extracts of Eucalyptus grandis (DPEC), characterized and developed by Brazilian Agricultural Research Corporation-Embrapa Temperate Agriculture (EMBRAPA-CPACT), were evaluated for antimicrobial activity against Candida albicans, Streptococcus mutans, and Lactobacillus acidophilus by direct contact test. Further, their capacity for the prevention of teeth enamel demineralization and cytotoxicity in vitro were also determined. The natural polymers were tested at different concentrations (1500-7500 µg mL-1) and the formulation of an experimental fluoride varnish with antimicrobial activity was evaluated by direct contact test, whereas cytotoxicity was analyzed through the colorimetric MTT assay. Preliminary data showed no statistically significant differences in cytotoxicity to NIH/3T3 cell line when DPEC is compared to the control group. On the other hand, the antimicrobial capacity and demineralization effects were found between the test groups at the different concentrations tested. Chitosan films containing distilled pyroligneous extracts of E. grandis may be an effective control strategy to prevent biofilm formation related to dental caries when applied as a protective varnish. They may inhibit the colonization of oral microorganisms and possibly control dental caries through a decrease in pH and impairment of enamel demineralization.

The role of CACNA1C gene and childhood trauma interaction on bipolar disorder.

Studies on gene x environment interaction (GxE) have provided vital information for uncovering the origins of complex diseases. When considering the etiology of bipolar disorder (BD), the role of such interactions is unknown. Here, we tested whether trauma during childhood could modify the effect of two polymorphisms in the CACNA1C gene (rs1006737 and rs4765913) in terms of susceptibility to BD. The study enrolled 878 Caucasian young adults in a cross-sectional population-based survey. BD diagnosis was performed using a clinical interview MINI 5.0, and trauma was assessed with the childhood trauma questionnaire (CTQ). Binary logistic regression models were employed to test the main effects of polymorphisms, haplotypes, and GxE interactions using sex as a confounder. We did not observe an association between the polymorphisms and diagnosis of BD. However, we noted that childhood trauma modified the effect of the rs4765913 polymorphism (p = .018) and the AA haplotype (rs1006737 - rs4765913) (p = .018) on BD susceptibility. A allele carriers of the rs4765913 polymorphism or the AA haplotype exposed to childhood trauma are more likely to develop BD compared to the individuals without a genetic risk. Thus, this study showed that the risk of developing BD in individuals exposed to childhood trauma was influenced by the individual's genetic background, varying according to the CACNA1C genotypes.

Inosine prevents hyperlocomotion in a ketamine-induced model of mania in rats.

Bipolar Disorder is a disorder characterized by alternating episodes of depression, mania or hypomania, or even mixed episodes. The treatment consists on the use of mood stabilizers, which imply serious adverse effects. Therefore, it is necessary to identify new therapeutic targets to prevent or avoid new episodes. Evidence shows that individuals in manic episodes present a purinergic system dysfunction. In this scenario, inosine is a purine nucleoside known to act as an agonist of A1 and A2A adenosine receptors. Thus, we aimed to elucidate the preventive effect of inosine on locomotor activity, changes in purine levels, and adenosine receptors density in a ketamine-induced model of mania in rats. Inosine pretreatment (25 mg/kg, oral route) prevented the hyperlocomotion induced by ketamine (25 mg/kg, intraperitoneal route) in the open-field test; however, there was no difference in hippocampal density of A1 and A2A receptors, where ketamine, as well as inosine, were not able to promote changes in immunocontent of the adenosine receptors. Likewise, no effects of inosine pretreatments or ketamine treatment were observed for purine and metabolic residue levels evaluated. In this sense, we suggest further investigation of signaling pathways involving purinergic receptors, using pharmacological strategies to better elucidate the action mechanisms of inosine on bipolar disorder. Despite the limitations, inosine administration could be a promising candidate for bipolar disorder treatment, especially by attenuating maniac phase symptoms, once it was able to prevent the hyperlocomotion induced by ketamine in rats.