Duplications in ADHD patients harbour neurobehavioural genes that are co-expressed with genes associated with hyperactivity in the mouse

Attention deficit/hyperactivity disorder (ADHD) is a childhood onset disorder, prevalent in 5.3% of children and 1–4% of adults. ADHD is highly heritable, with a burden of large (>500 Kb) copy number variants (CNVs) identified among individuals with ADHD. However, how such CNVs exert their effects is poorly understood. We examined the genes affected by 71 large, rare, and predominantly inherited CNVs identified among 902 individuals with ADHD. We applied both mouse‐knockout functional enrichment analyses, exploiting behavioral phenotypes arising from the determined disruption of 1:1 mouse orthologues, and human brain‐specific spatio‐temporal expression data to uncover molecular pathways common among genes contributing to enriched phenotypes. Twenty‐two percent of genes duplicated in individuals with ADHD that had mouse phenotypic information were associated with abnormal learning/memory/conditioning (“l/m/c”) phenotypes. Although not observed in a second ADHD‐cohort, we identified a similar enrichment among genes duplicated by eight de novo CNVs present in eight individuals with Hyperactivity and/or Short attention span (“Hyperactivity/SAS”, the ontologically‐derived phenotypic components of ADHD). In the brain, genes duplicated in patients with ADHD and Hyperactivity/SAS and whose orthologues’ disruption yields l/m/c phenotypes in mouse (“candidate‐genes”), were co‐expressed with one another and with genes whose orthologues’ mouse models exhibit hyperactivity. Moreover, genes associated with hyperactivity in the mouse were significantly more co‐expressed with ADHD candidate‐genes than with similarly identified genes from individuals with intellectual disability. Our findings support an etiology for ADHD distinct from intellectual disability, and mechanistically related to genes associated with hyperactivity phenotypes in other mammalian species

GeneNet toolbox for MATLAB: a flexible platform for the analysis of gene connectivity in biological networks

We present GeneNet Toolbox for MATLAB (also available as a set of standalone applications for Linux). The toolbox, available as command-line or with a graphical user interface, enables biologists to assess connectivity among a set of genes of interest (‘seed-genes’) within a biological network of their choosing. Two methods are implemented for calculating the significance of connectivity among seed-genes: ‘seed randomization’ and ‘network permutation’. Options include restricting analyses to a specified subnetwork of the primary biological network, and calculating connectivity from the seed-genes to a second set of interesting genes. Pre-analysis tools help the user choose the best connectivity-analysis algorithm for their network. The toolbox also enables visualization of the connections among seed-genes. GeneNet Toolbox functions execute in reasonable time for very large networks (∼10 million edges) on a desktop computer

GeneFEAST: the pivotal, gene-centric step in functional enrichment analysis interpretation

Summary: GeneFEAST, implemented in Python, is a gene-centric functional enrichment analysis summarisation and visualisation tool that can be applied to large functional enrichment analysis (FEA) results arising from upstream FEA pipelines. It produces a systematic, navigable HTML report, making it easy to identify sets of genes putatively driving multiple enrichments and to explore gene-level quantitative data first used to identify input genes. Further, GeneFEAST can compare FEA results from multiple studies, making it possible, for example, to highlight patterns of gene expression amongst genes commonly differentially expressed in two sets of conditions, and giving rise to shared enrichments under those conditions. GeneFEAST offers a novel, effective way to address the complexities of linking up many overlapping FEA results to their underlying genes and data, advancing gene-centric hypotheses, and providing pivotal information for downstream validation experiments. Availability: GeneFEAST is available at https://github.com/avigailtaylor/GeneFEAST Contact: [email protected]: Main text: 3 pages, 1 figure. Supplementary Information: 16 pages, 3 figures, 2 tables, 4 boxe

Duplications in ADHD patients harbour neurobehavioural genes that are co‐expressed with genes associated with hyperactivity in the mouse

Attention deficit/hyperactivity disorder (ADHD) is a childhood onset disorder, prevalent in 5.3% of children and 1–4% of adults. ADHD is highly heritable, with a burden of large (>500 Kb) copy number variants (CNVs) identified among individuals with ADHD. However, how such CNVs exert their effects is poorly understood. We examined the genes affected by 71 large, rare, and predominantly inherited CNVs identified among 902 individuals with ADHD. We applied both mouse‐knockout functional enrichment analyses, exploiting behavioral phenotypes arising from the determined disruption of 1:1 mouse orthologues, and human brain‐specific spatio‐temporal expression data to uncover molecular pathways common among genes contributing to enriched phenotypes. Twenty‐two percent of genes duplicated in individuals with ADHD that had mouse phenotypic information were associated with abnormal learning/memory/conditioning (“l/m/c”) phenotypes. Although not observed in a second ADHD‐cohort, we identified a similar enrichment among genes duplicated by eight de novo CNVs present in eight individuals with Hyperactivity and/or Short attention span (“Hyperactivity/SAS”, the ontologically‐derived phenotypic components of ADHD). In the brain, genes duplicated in patients with ADHD and Hyperactivity/SAS and whose orthologues’ disruption yields l/m/c phenotypes in mouse (“candidate‐genes”), were co‐expressed with one another and with genes whose orthologues’ mouse models exhibit hyperactivity. Moreover, genes associated with hyperactivity in the mouse were significantly more co‐expressed with ADHD candidate‐genes than with similarly identified genes from individuals with intellectual disability. Our findings support an etiology for ADHD distinct from intellectual disability, and mechanistically related to genes associated with hyperactivity phenotypes in other mammalian species. © 2015 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc

Clusters of 33 genes whose products have known protein-protein interactions copy changed among 34 (22%) of 154 patients with intellectual disability.

<p>These genes were those identified using two or more methods (from KEGG, GO and Gene Expression clustering) and that were found to contribute to a significant enrichment of interactions identified by the Dapple protein-protein interaction network (<i>p</i> < 1x10^–4).</p

Forty non-exclusive patient groups, each group’s patients sharing the same HPO term, amongst whom individual copy number variant candidate genes were each recurrently identified by multiple functional genomics methods and whose recurrently-identified candidate genes demonstrated a significant number of protein-protein interactions.

<p>The dendrogram displays the relationship between categories based upon the number of candidate genes identified by multiple methods that are shared between the phenotype-group patients. Categories are marked if there were significant enrichments using clustering in a gene expression network (Blue), GO (Green) or KEGG (yellow). No phenotype-grouped patients with candidate genes meeting these criteria were identified use mouse KO phenotype (MGI) associations.</p

Functional genomics enrichments significantly enriched in genes affected by <i>de novo</i> CNVs in 33 patients presenting with seizures.

<p><b>(A)</b> Significant functional genomics enrichments. Many of these functions have links to seizures or associated phenomena (synaptic deficits, receptor signaling, gustatory aura[<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005012#pgen.1005012.ref073" target="_blank">73</a>]) but also to regions prone to copy number variation[<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005012#pgen.1005012.ref074" target="_blank">74</a>]. <b>(B)</b> Genes disrupted by short CNVs in patients were also observed to cluster significantly in a brain-specific gene co-expression network. Here we display the strongest clusters (<i>r ></i> 0.92 for all co-expression similarities) of genes from seizure patients from this network. <b>(C)</b> Overall, the functional enrichments identified known (HPO-defined) seizure genes for 11 of the 33 patients, and proposed causal genes for 21 of the remaining 22 patients.</p