The role of cadherin genes in five major psychiatric disorders: A literature update.

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.

Dopamine transporter genotype is associated with a lateralized resistance to distraction during attention selection.

Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional versus response selection. A sample of nonclinical adult humans (N = 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1; SLC6A3), which are argued to influence the level of available synaptic dopamine and confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and spatial cueing but not flanker tasks. Specifically, compared with individuals carrying one or two copies of the 10-repeat DAT1 allele, individuals without this allele demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None of these significant effects could be explained by speed-accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield.

An association between a dopamine transporter gene (SLC6A3) haplotype and ADHD symptom measures in nonclinical adults.

Previous genetic studies have postulated that attention deficit hyperactivity disorder (ADHD) should be regarded as the extreme end of a set of behavioural traits that can be continuously measured in the general population. The current study adopted a quantitative trait approach to examine the relationship between dopamine gene variants and self-reported ADHD symptoms in 517 nonclinical adults. Although genetic associations with variants of both the dopamine transporter (DAT1; SLC6A3) and D4 receptor (DRD4) genes have been reliably reported in children, results in adults are less consistent. We probed two potentially functional variable number of tandem repeat (VNTR) polymorphisms in the 3'UTR and intron 8 of DAT1, the 10-repeat and 6-repeat alleles of which respectively form a haplotype (10/6 DAT1 haplotype) that is associated with childhood ADHD. We also genotyped the exon 3 VNTR of DRD4, the 7-repeat allele of which is also an established risk factor for childhood ADHD. Permutation analysis showed an influence of the 10/6 DAT1 haplotype on both CAARS-G and CAARS-H (DSM-IV ADHD Symptoms Total and ADHD Index respectively), such that ADHD symptom scores increased with each additional copy of the 10/6 DAT1 haplotype. This result survived corrections for multiple comparisons both at the level of genotype and phenotype. A nominal association with CAARS-G was also found for the 7-repeat allele of the DRD4 VNTR however this did not survive multiple comparison correction. Our results provide further support for the influence of variation in the 10/6 DAT1 haplotype and individual differences in ADHD symptoms in adults.

Legionella pneumophila secretes a mitochondrial carrier protein during infection.

The Mitochondrial Carrier Family (MCF) is a signature group of integral membrane proteins that transport metabolites across the mitochondrial inner membrane in eukaryotes. MCF proteins are characterized by six transmembrane segments that assemble to form a highly-selective channel for metabolite transport. We discovered a novel MCF member, termed Legionellanucleotide carrier Protein (LncP), encoded in the genome of Legionella pneumophila, the causative agent of Legionnaire's disease. LncP was secreted via the bacterial Dot/Icm type IV secretion system into macrophages and assembled in the mitochondrial inner membrane. In a yeast cellular system, LncP induced a dominant-negative phenotype that was rescued by deleting an endogenous ATP carrier. Substrate transport studies on purified LncP reconstituted in liposomes revealed that it catalyzes unidirectional transport and exchange of ATP transport across membranes, thereby supporting a role for LncP as an ATP transporter. A hidden Markov model revealed further MCF proteins in the intracellular pathogens, Legionella longbeachae and Neorickettsia sennetsu, thereby challenging the notion that MCF proteins exist exclusively in eukaryotic organisms.

Ancestral and derived protein import pathways in the mitochondrion of Reclinomonas americana.

The evolution of mitochondria from ancestral bacteria required that new protein transport machinery be established. Recent controversy over the evolution of these new molecular machines hinges on the degree to which ancestral bacterial transporters contributed during the establishment of the new protein import pathway. Reclinomonas americana is a unicellular eukaryote with the most gene-rich mitochondrial genome known, and the large collection of membrane proteins encoded on the mitochondrial genome of R. americana includes a bacterial-type SecY protein transporter. Analysis of expressed sequence tags shows R. americana also has components of a mitochondrial protein translocase or "translocase in the inner mitochondrial membrane complex." Along with several other membrane proteins encoded on the mitochondrial genome Cox11, an assembly factor for cytochrome c oxidase retains sequence features suggesting that it is assembled by the SecY complex in R. americana. Despite this, protein import studies show that the RaCox11 protein is suited for import into mitochondria and functional complementation if the gene is transferred into the nucleus of yeast. Reclinomonas americana provides direct evidence that bacterial protein transport pathways were retained, alongside the evolving mitochondrial protein import machinery, shedding new light on the process of mitochondrial evolution.

Hijacking mitochondria: bacterial toxins that modulate mitochondrial function.

Bacterial infection has enormous global social and economic impacts stemming from effects on human health and agriculture. Although there are still many unanswered questions, decades of research has uncovered many of the pathogenic mechanisms at play. It is now clear that bacterial pathogens produce a plethora of proteins known as "toxins" and "effectors" that target a variety of physiological host processes during the course of infection. One of the targets of host targeted bacterial toxins and effectors are the mitochondria. The mitochondrial organelles are major players in many biological functions, including energy conversion to ATP and cell death pathways, which inherently makes them targets for bacterial proteins. We present a summary of the toxins targeted to mitochondria and for those that have been studied in finer detail, we also summarize what we know about the mechanisms of targeting and finally their action at the organelle.

From evolution to pathogenesis: the link between ß-barrel assembly machineries in the outer membrane of mitochondria and gram-negative bacteria.

ß-barrel proteins are the highly abundant in the outer membranes of Gram-negative bacteria and the mitochondria in eukaryotes. The assembly of ß-barrels is mediated by two evolutionary conserved machineries; the ß-barrel Assembly Machinery (BAM) in Gram-negative bacteria; and the Sorting and Assembly Machinery (SAM) in mitochondria. Although the BAM and SAM have functionally conserved roles in the membrane integration and folding of ß-barrel proteins, apart from the central BamA and Sam50 proteins, the remaining components of each of the complexes have diverged remarkably. For example all of the accessory components of the BAM complex characterized to date are located in the bacterial periplasm, on the same side as the N-terminal domain of BamA. This is the same side of the membrane as the substrates that are delivered to the BAM. On the other hand, all of the accessory components of the SAM complex are located on the cytosolic side of the membrane, the opposite side of the membrane to the N-terminus of Sam50 and the substrate receiving side of the membrane. Despite the accessory subunits being located on opposite sides of the membrane in each system, it is clear that each system is functionally equivalent with bacterial proteins having the ability to use the eukaryotic SAM and vice versa. In this review, we summarize the similarities and differences between the BAM and SAM complexes, highlighting the possible selecting pressures on bacteria and eukaryotes during evolution. It is also now emerging that bacterial pathogens utilize the SAM to target toxins and effector proteins to host mitochondria and this will also be discussed from an evolutionary perspective.

Generation of four iPSC lines from peripheral blood mononuclear cells (PBMCs) of an attention deficit hyperactivity disorder (ADHD) individual and a healthy sibling in an Australia-Caucasian family.

Peripheral blood mononuclear cells were donated by a male teenager with clinically diagnosed attention deficit hyperactivity disorder (ADHD) under the Diagnostic and Statistical Manual of Mental Disorders IV criteria and his unaffected male sibling. Induced pluripotent stem cells were developed using integration-free Sendai Reprogramming factors containing OCT4, SOX2, KLF4, and c-MYC. All four iPSC lines displayed pluripotent cell morphology, pluripotency-associated factors at the DNA and protein level, alkaline phosphatase enzymatic activity and a male karyotype of 46, XY. All lines had capacity for in vitro differentiation into all the three germ layers. All were negative for Mycoplasma.

Allelic variation in dopamine D2 receptor gene is associated with attentional impulsiveness on the Barratt Impulsiveness Scale (BIS-11).

OBJECTIVES: Previous studies have postulated that noradrenergic and/or dopaminergic gene variations are likely to underlie individual differences in impulsiveness, however, few have shown this. The current study examined the relationship between catecholamine gene variants and self-reported impulsivity, as measured by the Barratt Impulsiveness Scale (Version 11; BIS-11) Methods: Six hundred and seventy-seven non-clinical adults completed the Barratt Impulsiveness Scale (BIS-11). DNA was analysed for a set of 142 single-nucleotide polymorphisms (SNPs) across 20 autosomal catecholamine genes. Association was tested using an additive regression model with permutation testing used to control for the influence of multiple comparison. RESULTS: Analysis revealed an influence of rs4245146 of the dopamine D2 receptor (DRD2) gene on the BIS-11 attention first-order factor, such that self-reported attentional impulsiveness increased in an additive fashion with each copy of the T allele. CONCLUSIONS: These findings provide preliminary evidence that allelic variation in DRD2 may influence impulsiveness by increasing the propensity for attentional lapses.

Genome-wide association study reveals novel genetic locus associated with intra-individual variability in response time.

Intra-individual response time variability (IIRTV) is proposed as a viable endophenotype for many psychiatric disorders, particularly attention-deficit hyperactivity disorder (ADHD). Here we assessed whether IIRTV was associated with common DNA variation genome-wide and whether IIRTV mediated the relationship between any associated loci and self-reported ADHD symptoms. A final data set from 857 Australian young adults (489 females and 368 males; Mage = 22.14 years, SDage = 4.82 years) who completed five response time tasks and self-reported symptoms of ADHD using the Conners' Adult ADHD Rating Scale was used. Principal components analysis (PCA) on these response time measures (standard deviation of reaction times and the intra-individual coefficient of variation) produced two variability factors (labelled response selection and selective attention). To understand the genetic drivers of IIRTV we performed a genome-wide association analysis (GWAS) on these PCA-derived indices of IIRTV. For the selective attention variability factor, we identified one single-nucleotide polymorphism (SNP) attaining genome-wide significance; rs62182100 in the HDAC4 gene located on chromosome 2q37. A bootstrapping mediation analysis demonstrated that the selective attention variability factor mediated the relationship between rs62182100 and self-reported ADHD symptoms. Our findings provide the first evidence of a genome-wide significant SNP association with IIRTV and support the potential utility of IIRTV as a valid endophenotype for ADHD symptoms. However, limitations of this study suggest that these observations should be interpreted with caution until replication samples become available.

A case-control genome-wide association study of ADHD discovers a novel association with the tenascin R (TNR) gene.

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.

Identification and functional characterisation of a novel dopamine beta hydroxylase gene variant associated with attention deficit hyperactivity disorder.

OBJECTIVES: Dysregulation in neurotransmitter signalling has been implicated in the aetiology of attention deficit hyperactivity disorder (ADHD). Polymorphisms of the gene encoding dopamine beta hydroxylase (DBH) have been reported to be associated with ADHD; however, small sample sizes have led to inconsistency. METHODS: We conducted transmission disequilibrium test analysis in 794 nuclear families to examine the relationship between DBH and ADHD. The effects of the ADHD-associated polymorphisms on gene expression were assessed by luciferase reporter assays in a human neuroblastoma cell line, SH-SY5Y. RESULTS: A SNP within the 3' untranslated region of DBH rs129882 showed a significant association with ADHD (χ(2) = 9.71, p = 0.0018, OR = 1.37). This association remained significant after Bonferroni correction for multiple testing (p = 0.02). Further, allelic variation in rs129882 significantly impacted luciferase expression. Specifically, the C allele of the ADHD-associated rs129882 SNP produced a 2-fold decrease (p < 0.001) in luciferase activity. CONCLUSIONS: These data demonstrate for the first time that a DBH gene variant, rs129882, which confers risk to ADHD is also associated with reduced in vitro gene expression. Reduced DBH expression would be consistent with decreased conversion of dopamine to noradrenaline and thus with a relative hypo-noradrenergic state in ADHD.