Global DNA methylation patterns in Alcohol Use Disorder.

Alcohol Use Disorder (AUD) is a highly prevalent condition worldwide that produces a wide range of pathophysiological consequences, with a critical impact on health and social issues. Alcohol influences gene expression through epigenetic changes mainly through DNA methylation. In this sense, levels of 5-methylcytosine (5-mC), namely Global DNA methylation (GMe), which can be influenced by environmental and hormonal effects, represent a putative biological mechanism underlying alcohol effects. Our aim was to investigate the influence of AUD diagnosis and alcohol patterns (i.e., years of addiction, use in the last 30 days, and alcohol severity) on GMe levels. The sample consisted of 256 men diagnosed with AUD and 361 men without AUD. DNA samples from peripheral blood were used to assess GMe levels, measured through the levels of 5-mC using high-performance liquid chromatography. Results from multiple linear regression analysis indicated that the presence of AUD was associated with lower GMe levels (beta=-0.155, p=0.011). Other alcohol-related outcomes were not associated with DNA methylation. Our findings are consistent with the hypothesis that the impact of chronic and heavy alcohol use in GMe could be a potential mechanism mediating the multiple organ damages related to AUD.

Global DNA methylation changes in adults with attention deficit-hyperactivity disorder and its comorbidity with bipolar disorder: links with polygenic scores.

Genetic and environmental factors contribute to the etiology of Attention Deficit-Hyperactivity Disorder (ADHD). In this sense, the study of epigenetic mechanisms could contribute to the understanding of the disorder's neurobiology. Global DNA methylation (GMe) evaluated through 5-methylcytosine levels could be a promising epigenetic biomarker to capture long-lasting biological effects in response to environmental and hormonal changes. We conducted the first assessment of GMe levels in subjects with ADHD (n = 394) and its main comorbidities in comparison to populational controls (n = 390). Furthermore, given the high genetic contribution to ADHD (heritability of 80%), polygenic risk scores (PRS) were calculated to verify the genetic contribution to GMe levels in ADHD and the comorbidities associated with GMe levels. The GMe levels observed in patients were lower than controls (P = 1.1e-8), with women being significantly less globally methylated than men (P = 0.002). Regarding comorbidities, the presence of bipolar disorder (BD) among patients with ADHD was associated with higher methylation levels compared to patients with ADHD without BD (P = 0.031). The results did not change when pharmacological treatment was accounted for in the analyses. The ADHD and BD most predictive PRSs were negatively (P = 0.0064) and positively (P = 0.0042) correlated with GMe, respectively. This study is the first to report an association between GMe, ADHD, and its comorbidity with BD and associations between PRSs for specific psychiatric disorders and GMe. Our findings add to previous evidence that GMe may be a relevant piece in the psychiatric disorders' etiological landscape.

The role of glucocorticoid receptor gene in the association between attention deficit-hyperactivity disorder and smaller brain structures.

ADHD is associated with smaller subcortical brain volumes and cortical surface area, with greater effects observed in children than adults. It is also associated with dysregulation of the HPA axis. Considering the effects of the glucocorticoid receptor (NR3C1) in neurophysiology, we hypothesize that the blurred relationships between brain structures and ADHD in adults could be partly explained by NR3C1 gene variation. Structural T1-weighted images were acquired on a 3 T scanner (N = 166). Large-scale genotyping was performed, and it was followed by quality control and pruning procedures, which resulted in 48 independent NR3C1 gene variants analyzed. After a stringent Bonferroni correction, two SNPs (rs2398631 and rs72801070) moderated the association between ADHD and accumbens and amygdala volumes in adults. The significant SNPs that interacted with ADHD appear to have a role in gene expression regulation, and they are in linkage disequilibrium with NR3C1 variants that present well-characterized physiological functions. The literature-reported associations of ADHD with accumbens and amygdala were only observed for specific NR3C1 genotypes. Our findings reinforce the influence of the NR3C1 gene on subcortical volumes and ADHD. They suggest a genetic modulation of the effects of a pivotal HPA axis component in the neuroanatomical features of ADHD.

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

OBJECTIVE: 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.

Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.

IMPORTANCE: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. OBJECTIVE: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. MAIN OUTCOMES AND MEASURES: Interregional profiles of group difference in cortical thickness between cases and controls. RESULTS: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. CONCLUSIONS AND RELEVANCE: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

The association between SYT1-rs2251214 and cocaine use disorder further supports its role in psychiatry.

Synaptotagmin-1 is an essential regulator of synaptic vesicle exocytosis, and its encoding gene (SYT1) is a genome and transcriptome-wide association hit in cognitive performance, personality and cocaine use disorder (CUD) studies. Additionally, in candidate gene studies the specific variant rs2251214 has been associated with attention-deficit/hyperactivity disorder (ADHD), antisocial personality disorder and other externalizing phenotypes in adults with ADHD, as well as with response to methylphenidate (MPH) treatment. In this context, we sought to evaluate, in an independent sample, the association of this variant with CUD, a phenotype that shares common biological underpinnings with the previously associated traits. We tested the association between SYT1-rs2251214 and CUD susceptibility and severity (addiction severity index) in a sample composed by 315 patients addicted to smoked cocaine and 769 non-addicted volunteers. SYT1-rs2251214 was significantly associated with susceptibility to CUD, where the G allele presented increased risk for the disorder in the genetic models tested (P = 0.0021, OR = 1.44, allelic; P = 0.0012, OR = 1.48, additive; P = 0.0127, OR = 1.41, dominant). This is the same allele that was associated with increased risk for ADHD and other externalizing behaviors, as well as poor response to MPH treatment in previous studies. These findings suggest that the neurotransmitter exocytosis pathway might play a critical role in the liability for psychiatric disorders, especially externalizing behaviors and CUD.