A polygenic risk score analysis of ASD and ADHD across emotion recognition subtypes

This study investigated the genetic components of ADHD and ASD by examining the cross-disorder trait of emotion recognition problems. The genetic burden for ADHD and ASD on previously identified emotion recognition factors (speed and accuracy of visual and auditory emotion recognition) and classes (Class 1: Average visual, impulsive auditory; Class 2: Average-strong visual & auditory; Class 3: Impulsive & imprecise visual, average auditory; Class 4: Weak visual & auditory) was assessed using ASD and ADHD polygenic risk scores (PRS). Our sample contained 552 participants: 74 with ADHD, 85 with ASD, 60 with ASD + ADHD, 177 unaffected siblings of ADHD or ASD probands, and 156 controls. ADHD- and ASD-PRS, calculated from the latest ADHD and ASD GWAS meta-analyses, were analyzed across these emotion recognition factors and classes using linear mixed models. Unexpectedly, the analysis of emotion recognition factors showed higher ASD-PRS to be associated with faster visual emotion recognition. The categorical analysis of emotion recognition classes showed ASD-PRS to be reduced in Class 3 compared to the other classes (p value threshold [pT] = 1, p = .021). A dimensional analysis identified a high ADHD-PRS reduced the probability of being assigned to the Class 1 or Class 3 (pT = .05, p = .028 and p = .044, respectively). Though these nominally significant results did not pass FDR correction, they potentially indicate different indirect causative chains from genetics via emotion recognition to ADHD and ASD, which need to be verified in future research

Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures

Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N = 10,720-10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10−3) and BMI (P = 1.63 × 10−5); the circadian rhythm was associated with BMI (P = 1.28 × 10−3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P = 7.7 × 10−3; replication data P = 3.9 × 10−2) a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions

Integrative genomic analysis of methylphenidate response in attention-deficit/hyperactivity disorder

Methylphenidate (MPH) is the most frequently used pharmacological treatment in children with attention-deficit/hyperactivity disorder (ADHD). However, a considerable interindividual variability exists in clinical outcome. Thus, we performed a genome-wide association study of MPH efficacy in 173 ADHD paediatric patients. Although no variant reached genome-wide significance, the set of genes containing single-nucleotide polymorphisms (SNPs) nominally associated with MPH response (P < 0.05) was significantly enriched for candidates previously studied in ADHD or treatment outcome. We prioritised the nominally significant SNPs by functional annotation and expression quantitative trait loci (eQTL) analysis in human brain, and we identified 33 SNPs tagging cis-eQTL in 32 different loci (referred to as eSNPs and eGenes, respectively). Pathway enrichment analyses revealed an over-representation of genes involved in nervous system development and function among the eGenes. Categories related to neurological diseases, psychological disorders and behaviour were also significantly enriched. We subsequently meta-analysed the association with clinical outcome for the 33 eSNPs across the discovery sample and an independent cohort of 189 ADHD adult patients (target sample) and we detected 15 suggestive signals. Following this comprehensive strategy, our results provide a better understanding of the molecular mechanisms implicated in MPH treatment effects and suggest promising candidates that may encourage future studies

Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response

Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPHinduced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following MPH treatment in rats, 98 DEPs were found (P 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

harrow : nova família de transposons de Drosophila envolvida em transferência horizontal

Os elementos transponíveis são conhecidos por possuírem a fascinante propriedade de mudarem de local dentro do genoma de suas espécies hospedeiras e mesmo de serem capazes de atravessar barreiras interespecíficas, invadindo novos genomas. Neste estudo, uma nova família de elementos transponíveis, denominada harrow, é descrita para a Superfamília hAT. Buscas por seqüências harrow foram realizadas em 65 espécies de Drosophilidae, sendo que a maior parte dessas espécies pertence a grupos Neotropicais do gênero Drosophila ou é cosmopolita. As seqüências harrow encontradas apresentam distribuições descontínuas ao longo do gênero Drosophila e apresentam altas similaridades entre si, inconsistentes com os tempos de divergência das espécies hospedeiras. Além disso, incongruências topológicas foram encontradas entre as filogenias de harrow e das espécies hospedeiras. Os resultados obtidos no presente estudo indicam que harrow provavelmente invadiu os genomas de seus hospedeiros por múltiplos eventos de transferência horizontal, os quais devem ter ocorrido entre espécies dos Trópicos do Novo Mundo. Estes resultados reforçam a visão de que eventos de transferências horizontais entre eucariotos são mais comuns do que se previa anteriormente.Transposable elements are known for their amazing properties of moving from one place to another inside the genome of their host species, as well as, for their ability to cross species boundaries, invading new genomes. In this study, a new family of transposable elements, harrow, is described for the hAT Superfamily of DNA transposons. Searches for harrow sequences were conducted in 65 Drosophilidae species, mainly representing Neotropical and cosmopolitan group species from genus Drosophila. The obtained harrow sequences show a patchy distribution along the genus Drosophila and present high sequence similarities, which are inconsistent with the divergence times of the host species. Additionally, topological incongruities were found between harrow and host species phylogenies. The results obtained in this study indicate that harrow has probably invaded its host genomes through multiple horizontal transfer events, which should have occurred in Neotropical regions. These results support the growing view that horizontal transfers between eukaryotes are more common than they have been thought before

harrow : nova família de transposons de Drosophila envolvida em transferência horizontal

Os elementos transponíveis são conhecidos por possuírem a fascinante propriedade de mudarem de local dentro do genoma de suas espécies hospedeiras e mesmo de serem capazes de atravessar barreiras interespecíficas, invadindo novos genomas. Neste estudo, uma nova família de elementos transponíveis, denominada harrow, é descrita para a Superfamília hAT. Buscas por seqüências harrow foram realizadas em 65 espécies de Drosophilidae, sendo que a maior parte dessas espécies pertence a grupos Neotropicais do gênero Drosophila ou é cosmopolita. As seqüências harrow encontradas apresentam distribuições descontínuas ao longo do gênero Drosophila e apresentam altas similaridades entre si, inconsistentes com os tempos de divergência das espécies hospedeiras. Além disso, incongruências topológicas foram encontradas entre as filogenias de harrow e das espécies hospedeiras. Os resultados obtidos no presente estudo indicam que harrow provavelmente invadiu os genomas de seus hospedeiros por múltiplos eventos de transferência horizontal, os quais devem ter ocorrido entre espécies dos Trópicos do Novo Mundo. Estes resultados reforçam a visão de que eventos de transferências horizontais entre eucariotos são mais comuns do que se previa anteriormente.Transposable elements are known for their amazing properties of moving from one place to another inside the genome of their host species, as well as, for their ability to cross species boundaries, invading new genomes. In this study, a new family of transposable elements, harrow, is described for the hAT Superfamily of DNA transposons. Searches for harrow sequences were conducted in 65 Drosophilidae species, mainly representing Neotropical and cosmopolitan group species from genus Drosophila. The obtained harrow sequences show a patchy distribution along the genus Drosophila and present high sequence similarities, which are inconsistent with the divergence times of the host species. Additionally, topological incongruities were found between harrow and host species phylogenies. The results obtained in this study indicate that harrow has probably invaded its host genomes through multiple horizontal transfer events, which should have occurred in Neotropical regions. These results support the growing view that horizontal transfers between eukaryotes are more common than they have been thought before