Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood. It is primarily characterised by high levels of activity, inattention, and impulsivity, and has strong negative impacts on academic functioning. Children with ADHD show a reduction in volume, and hypoactivity, in a range of brain regions. The underlying mechanisms behind these phenotypes are unknown, however, variants in several genes with known roles in neurodevelopment are associated with ADHD. In this review we discuss how these ADHD associated genes contribute to neurodevelopment, and how variants in these genes could give rise to the neurological phenotypes seen in ADHD.

Converging evidence from candidate gene, genome-wide linkage, and association studies support a role of cadherins in the pathophysiology of five major psychiatric disorders including attention deficit hyperactivity disorder, autism spectrum disorder (ASD), schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). These molecules are transmembrane proteins which act as cell adhesives by forming adherens junctions (AJs) to bind cells within tissues. Members of the cadherin superfamily are also involved in biological processes such as signal transduction and plasticity that have been implicated in the etiology of major psychiatric conditions. Although there are over 110 genes mapped to the cadherin superfamily, our literature survey showed that evidence of association with psychiatric disorders is strongest for CDH7, CHD11, and CDH13. Gene enrichment analysis showed that those cadherin genes implicated in psychiatric disorders were overrepresented in biological processes such as in cell-cell adhesion (GO:0007156 & GO:0098742) and adherens junction organization (GO:0034332). Further, cadherin genes were also mapped to processes that have been linked to the development of psychiatric disorders such as nervous system development (GO:0007399). To further understand the role of cadherin SNPs implicated in psychiatric disorders, we utilized an in silico computational pipeline to functionally annotate associated variants. This analysis yielded eight variants mapped to PCDH1-13, CDH7, CDH11, and CDH13 that are predicted to be biologically functional. Functional genomic evaluation is now required to understand the molecular mechanism by which these variants might confer susceptibility to psychiatric disorders.

It is well-established that there is a strong genetic contribution to the aetiology of attention deficit hyperactivity disorder (ADHD). Here, we employed a hypothesis-free genome-wide association study (GWAS) design in a sample of 480 clinical childhood ADHD cases and 1208 controls to search for novel genetic risk loci for ADHD. DNA was genotyped using Illumina’s Human Infinium PsychArray-24v1.2., and the data were subsequently imputed to the 1000 Genomes reference panel. Rigorous quality control and pruning of genotypes at both individual subject and single nucleotide polymorphism (SNP) levels was performed. Polygenic risk score (PGRS) analysis revealed that ADHD case–control status was explained by genetic risk for ADHD, but no other major psychiatric disorders. Logistic regression analysis was performed genome-wide to test the association between SNPs and ADHD case–control status. We observed a genome-wide significant association (p = 3.15E−08) between ADHD and rs6686722, mapped to the Tenascin R (TNR) gene. Members of this gene family are extracellular matrix glycoproteins that play a role in neural cell adhesion and neurite outgrowth. Suggestive evidence of associations with ADHD was observed for an additional 111 SNPs (⩽9.91E−05). Although intriguing, the association between DNA variation in the TNR gene and ADHD should be viewed as preliminary given the small sample size of this discovery dataset.

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder of childhood with a strong genetic component. Despite the success of mapping ADHD risk loci, little work has been done to experimentally verify the contribution of these loci to ADHD phenotypes. Meta-analysis of four genome-wide association studies in ADHD suggested CHMP7 as a predisposing gene for ADHD. A DNA variant (rs2294123) mapped to CHMP7 has been shown (via bioinformatic analysis) to have a high likelihood for functionality and correlate with reduced transcript levels. We used CRISPR-Cas9 genome editing to generate a chmp7 zebrafish model for ADHD. chmp7+/− fish showed comparable reductions in mRNA levels to individuals homozygous for the CHMP7 ADHD risk allele. These fish displayed significant hyperactivity over a 24-h period at 6 days post-fertilisation compared to chmp7+/+, but this effect did not persist into juvenile and adulthood stages. In addition, chmp7+/− fish had significantly smaller total brain volumes than chmp7+/+ fish. Finally, the hyperactivity at 6 days post-fertilisation was significantly reduced through the application of methylphenidate, a mainstay pharmacological treatment for ADHD. Overall, this study highlights an important role for CHMP7 in the neurodevelopment of ADHD, and demonstrates the utility of zebrafish for modelling the functional effects of genes conferring risk to ADHD.

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.