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.

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