Efeitos do TDAH e de variantes genéticas do receptor de glicocorticoide sobre volumes cerebrais

Vários estudos relacionaram o TDAH à uma desregulação do eixo hipotálamo-pituitária-adrenal (HPA), envolvido na resposta ao estresse, e a alterações neuroanatômicas, como a redução do volume de certas regiões cerebrais. O receptor de glicocorticoide (GR), codificado pelo gene NR3C1, desempenha um papel fundamental na resposta ao estresse. A ativação do fator de transcrição GR regula a expressão de um grande número de genes e tem efeitos rápidos na excitabilidade neuronal. Considerando as evidências que ligam a variação genética do eixo HPA em transtornos psiquiátricos e volumes cerebrais, nós hipotetizamos que a variação no NR3C1 poderia moderar a associação relatada entre o TDAH e volume subcortical cerebral. Para isso, avaliamos os volumes do accumbens, amígdala, caudado, hipocampo, putâmen e volume intracraniano em 100 adultos com TDAH e 60 controles avaliados no Hospital de Clínicas de Porto Alegre. O diagnóstico de TDAH seguiu os critérios do DSM-5 e a aquisição das imagens foi conduzida em um scanner Siemens Magnetom Spectra 3T. A genotipagem foi realizada pela plataforma Infinium PsychArray-24 BeadChip, com posterior seleção de polimorfismos baseados em filtros genômicos e agrupamento por desequilíbrio de ligação, resultando em 47 variantes independentes incluídas na análise final. Interações entre as variantes e o diagnóstico de TDAH nas seis regiões cerebrais investigadas foram avaliadas usando modelo linear geral seguido de correção para múltiplos testes. Análises in silico foram realizadas para avaliar potenciais efeitos funcionais dos SNPs significativamente associados nas análises de interação. Os volumes intracraniano e do hipocampo se mostraram menores em casos comparado aos controles. Dos polimorfismos incluídos nas análises finais, vários apresentaram efeitos opostos de acordo com o diagnóstico de TDAH, principalmente no accumbens e na amígdala. Os SNPs rs10052957 e rs41423247, com papéis funcionais definidos, encontraram-se entre aqueles com efeitos significativos. Análises in silico revelaram que os SNPs que sobreviveram à correção de múltiplos testes e que apresentaram potenciais efeitos funcionais estavam em desequilíbrio de ligação com o rs6198, um SNP conhecido por estabilizar a isoforma GRβ, aumentando sua expressão. Nossos resultados indicam que as diferenças de volume de regiões cerebrais em indivíduos com TDAH e controles podem ser influenciadas por variantes no gene codificador de GR.Several studies have suggested that ADHD is associated with dysregulation of the Hypothalamic–Pituitary–Adrenal (HPA) axis, involved in stress-response, and with neuroanatomic alterations, such as reduced volume in certain brain regions. The glucocorticoid receptor (GR), encoded by the NR3C1 gene, plays a pivotal role in the stress response. The activated GR transcription factor regulates the expression of a large number of genes, and it has rapid effects on neuronal excitability. Considering the evidence linking HPA axis genetic variation in psychiatric disorders and brain volumes, we hypothesize that variation in NR3C1 could moderate the reported association between ADHD and brain subcortical volume. For this purpose, we evaluated the volumes of accumbens, amygdala, caudate, hippocampus, putamen and intracranial volume in 100 adults with ADHD and 60 controls, assessed at Hospital de Clínicas de Porto Alegre. The diagnosis of ADHD followed DSM-5 criteria and the images acquisition were conducted in a Siemens Magnetom Spectra 3T scanner. Genotyping was performed on the Infinium PsychArray-24 BeadChip platform, with a posterior selection of polymorphisms based on genomic filters and pruning, resulting in 47 independent variants included in the final analysis. Interactions between variants and ADHD diagnosis on the six brain regions investigated were evaluated using general linear model followed by correction for multiple tests. In silico analyses were performed to assess the potential functionality effects for the SNPs significantly associated in the interaction analyses. The hippocampus and intracranial volumes were decreased in cases when compared to controls. Of the polymorphisms included in the final analyses, several presented opposite directions of effects according to ADHD status, mostly on accumbens and amygdala. The rs10052957 and rs41423247, with functional role described, were among the significant SNPs. In silico analyses revealed that the SNPs that survived multiple test correction and had potential functional effects were in strong Linkage Disequilibrium with rs6198, a SNP known for stabilize the isoform GRβ, increasing its expression. Our findings indicate that volume differences of specific brain regions in subjects with ADHD and controls might be influenced by variants in the GR encoding gene

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets

Attention-deficit; Brain asymmetry; Hyperactivity disorderDeficit de atención; Asimetría cerebral; Trastorno de hiperactividadDèficit d’atenció; Asimetria cerebral; Trastorn d'hiperactivitatObjective Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen’s d from −0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait

Reduced fronto-striatal volume in attention-deficit/hyperactivity disorder in two cohorts across the lifespan

Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with altered brain anatomy in neuroimaging studies. However, small and heterogeneous study samples, and the use of region-of-interest and tissue-specific analyses have limited the consistency and replicability of these effects. We used a data-driven multivariate approach to investigate neuroanatomical features associated with ADHD in two independent cohorts: the Dutch NeuroIMAGE cohort (n = 890, 17.2 years) and the Brazilian IMpACT cohort (n = 180, 44.2 years). Using independent component analysis of whole-brain morphometry images, 375 neuroanatomical components were assessed for association with ADHD. In both discovery (corrected-p = 0.0085) and replication (p = 0.032) cohorts, ADHD was associated with reduced volume in frontal lobes, striatum, and their interconnecting white-matter. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD in children, and for the first time show its relevance to ADHD in adults. The fact that the cohorts are from different continents and comprise different age ranges highlights the robustness of the findings

Complexo SNARE na susceptibilidade ao transtorno por uso de álcool

Background: The etiology of Alcohol Dependence is multifactorial, resulting from the interplay of environmental and genetic factors, including variants in neurotransmission related genes. In this sense, the Soluble NSF-Attachment Protein Receptors (SNARE) complex, which acts on neurotransmitter release, could play an important role in this disorder. The aim of the present study was to evaluate polymorphisms in SNARE complex genes (STX1A rs2228607; SYT1 rs1880867 and rs2251214; VAMP2 26 bp Ins/Del; SNAP25 rs6108461 and rs8636) in relation to Alcohol Dependence susceptibility. Methods: The sample comprised 115 men under inpatient treatment for with Alcohol Dependence and 308 non-dependent controls. Additionally, 278 men with Attention-Deficit/Hyperactivity Disorder (ADHD), of which 35 presented comorbidity with Alcohol Dependence were subsequently evaluated in order to replicate the association. Results: A nominal association was found between the VAMP2 26 bp Ins/Del polymorphism and susceptibility to Alcohol Dependence, where the Ins/Ins genotype showed a risk to this disorder (p = 0.012; OR = 2.21). This result was supported by the ADHD replication sample, where the Ins/Ins genotype was also more frequent among Alcohol Dependent cases (p = 0.008; OR = 5.26). Other polymorphisms and haplotype analyses did not reveal significant differences between cases and controls. Conclusion: Overall, the present study suggests that VAMP2 26 bp Ins/Del polymorphism, previously associated with ADHD, is also implicated in Alcohol Dependence susceptibility

Complexo SNARE na susceptibilidade ao transtorno por uso de álcool

Background: The etiology of Alcohol Dependence is multifactorial, resulting from the interplay of environmental and genetic factors, including variants in neurotransmission related genes. In this sense, the Soluble NSF-Attachment Protein Receptors (SNARE) complex, which acts on neurotransmitter release, could play an important role in this disorder. The aim of the present study was to evaluate polymorphisms in SNARE complex genes (STX1A rs2228607; SYT1 rs1880867 and rs2251214; VAMP2 26 bp Ins/Del; SNAP25 rs6108461 and rs8636) in relation to Alcohol Dependence susceptibility. Methods: The sample comprised 115 men under inpatient treatment for with Alcohol Dependence and 308 non-dependent controls. Additionally, 278 men with Attention-Deficit/Hyperactivity Disorder (ADHD), of which 35 presented comorbidity with Alcohol Dependence were subsequently evaluated in order to replicate the association. Results: A nominal association was found between the VAMP2 26 bp Ins/Del polymorphism and susceptibility to Alcohol Dependence, where the Ins/Ins genotype showed a risk to this disorder (p = 0.012; OR = 2.21). This result was supported by the ADHD replication sample, where the Ins/Ins genotype was also more frequent among Alcohol Dependent cases (p = 0.008; OR = 5.26). Other polymorphisms and haplotype analyses did not reveal significant differences between cases and controls. Conclusion: Overall, the present study suggests that VAMP2 26 bp Ins/Del polymorphism, previously associated with ADHD, is also implicated in Alcohol Dependence susceptibility