Using bacterial artificial chromosome (BAC) array comparative genome hybridization (aCGH) at approximately 1.4 Mbp resolution, we screened post-mortem brain DNA from bipolar disorder cases, schizophrenia cases and control individuals (n=35 each) for DNA copy-number aberrations. DNA copy number is a largely unexplored source of human genetic variation that may contribute risk for complex disease. We report aberrations at four loci which were seen in affected but not control individuals, and which were verified by quantitative real-time PCR. These aberrant loci contained the genes encoding EFNA5, GLUR7, CACNG2 and AKAP5; all brain-expressed proteins with known or postulated roles in neuronal function, and three of which (GLUR7, CACNG2 and AKAP5) are involved in glutamate signaling. A second cohort of psychiatric samples was also tested by quantitative PCR using the primer/probe sets for EFNA5, GLUR7, CACNG2 and AKAP5, and samples with aberrant copy number were found at three of the four loci (GLUR7, CACNG2 and AKAP5). Further scrutiny of these regions may reveal insights into the etiology and genetic risk factors for these complex psychiatric disorders.
"Most of them are altered in bipolar disorder (Bernstein et al. 2013). A study of CNVs in bipolar disorder and schizophrenia cases that map to locicontaining brain-expressed genes, proves AKAP5 is included in neuronal function (Wilson et al. 2006). The increased copy number of AKAP5 is confirmed in a single bipolar-disorder sample. "
[Show abstract][Hide abstract] ABSTRACT: Objective:
Kinase Anchoring Proteins (AKAPs) have evolved to regulate the spatial and temporal organization of cellular signal transduction. As a typical member, AKAP5 which consisting of three orthologues: bovine AKAP75, rodent AKAP150 and human AKAP79, is the best known model in the anchoring and targeting properties. It is shown that AKAP5 can bind β2-adrenergic receptor, which is a member of GPCR superfamily, and orchestrate the interactions of various protein kinases, protein phosphatases and cytoskeletal element. AKAP5 is originally identified as a component of the postsynaptic density in neurons and plays a vital role in modulating neuronal activities. Subsequently, the AKAP5 complexes are also detected in other tissues and participated in various processes.
"and 22q deletions with autism (Kumar et al, 2008; Marshall et al, 2008; Mefford et al, 2009; Sebat et al, 2007; Weiss et al, 2008) and the 15q13.3 and 1q21.1 deletions with schizophrenia (International Schizophrenia Consortium, 2008; Stefansson et al, 2008; Vrijenhoek et al, 2008; Wilson et al, 2006; Xu et al, 2008). There is no published GWAS that has systematically evaluated CNVs in SD, although such variation may be important in regulating the phenotype. "
[Show abstract][Hide abstract] ABSTRACT: Single nucleotide polymorphisms that have been associated with opioid dependence (OD) altogether account for only a small proportion of the known heritability. Most of the genetic risk factors are unknown. Some of the "missing heritability" might be explained by copy number variations (CNVs) in the human genome. We used Illumina HumanOmni1 arrays to genotype 5,152 African-American and European-American OD cases and screened controls and implemented combined CNV calling methods. After quality control measures were applied, a genomewide association study (GWAS) of CNVs with OD was performed. For common CNVs, two deletions and one duplication were significantly associated with OD genomewide (e.g., P=2 × 10(-8) and OR (95% CI)=0.64 (0.54-0.74) for a chromosome 18q12.3 deletion). Several rare or unique CNVs showed suggestive or marginal significance with large effect sizes. This study is the first GWAS of OD using CNVs. Some identified CNVs harbor genes newly identified here to be of biological importance in addiction, while others affect genes previously known to contribute to substance dependence risk. Our findings augment our specific knowledge of the importance of genomic variation in addictive disorders, and provide an addiction CNV pool for further research. These findings require replication.Neuropsychopharmacology accepted article preview online, 27 October 2014. doi:10.1038/npp.2014.290.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2014; 40(4). DOI:10.1038/npp.2014.290 · 7.05 Impact Factor
"However, a recent study failed to find alterations in AMPA and kainate receptor subunits gene expression in the prefrontal cortex (PFC) of postmortem BD patients' tissue (Lyddon et al., 2012), while two single SNP markers within the GRIK4 gene (which encodes for the KA1 subtype of kainate receptors) and a haplotype have recently been associated with a protective effect against BD (Pickard et al., 2006). Other genetic studies have reported that patients with BD exhibit aberrant DNA copy number at several loci containing genes involved in glutamate signalling, including the GluR7 gene that encodes for a kainate receptor subunit (Wilson et al., 2006). Indeed, polymorphisms in GRIN1, GRIN2A, and GRIN2B genes, encoding for NMDA receptor subunits, have been reported to confer susceptibility to BD (Itokawa et al., 2003; Martucci et al., 2006; Mundo et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Aberrant synaptic plasticity, originating from abnormalities in dopamine and/or glutamate transduction pathways, may contribute to the complex clinical manifestations of bipolar disorder (BD). Dopamine and glutamate systems cross-talk at multiple levels, such as at the postsynaptic density (PSD). The PSD is a structural and functional protein mesh implicated in dopamine and glutamate-mediated synaptic plasticity. Proteins at PSD have been demonstrated to be involved in mood disorders pathophysiology and to be modulated by antipsychotics and mood stabilizers. On the other side, post-receptor effectors such as protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and the extracellular signal-regulated kinase (Erk), which are implicated in both molecular abnormalities and treatment of BD, may interact with PSD proteins, and participate in the interplay of the dopamine-glutamate signalling pathway. In this review, we describe emerging evidence on the molecular cross-talk between dopamine and glutamate signalling in BD pathophysiology and pharmacological treatment, mainly focusing on dysfunctions in PSD molecules. We also aim to discuss future therapeutic strategies that could selectively target the PSD-mediated signalling cascade at the crossroads of dopamine-glutamate neurotransmission.
Journal of Psychopharmacology 02/2014; 28(6). DOI:10.1177/0269881114523864 · 3.59 Impact Factor
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