Gene Expression and Genetic Variation Data Implicate PCLO in Bipolar Disorder

Choi, Kwang Ho; Higgs, Brandon W.; Wendland, Jens R.; Song, Jian; McMahon, Francis J.; Webster, Maree J.

doi:10.1016/j.biopsych.2010.09.042

Cited by 57 publications

(46 citation statements)

References 54 publications

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“…Since ARHGEF6/7 are known to bridge between GIT1 and PAKs, this reduced association may be due to alteration of the GIT1-ARHGEF6/7-PAK complex. Given the location of R283W, this variant may also affect the association of GIT1 with other key synaptic proteins associated with psychiatric disease genetic risk, such as the presynaptic cytomatrix protein PCLO (Piccolo) and PPFIA2 (Protein Tyrosine Phosphatase, Receptor Type, F Polypeptide (PTPRF), Interacting Protein (Liprin), Alpha 2) (14, 47). Another interesting question is why GIT1-S601N has similar defects to GIT1-R283W, given that S601 is located well outside of the SHD domain of GIT1 in a region with no defined structural domain.…”

Section: Discussionmentioning

confidence: 99%

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1–PAK3 signaling in neuroplasticity

et al. 2016

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While the pathogenesis of schizophrenia (SCZ) is proposed to involve alterations of neural circuits via synaptic dysfunction, the underlying molecular mechanisms remain poorly understood. Recent exome sequencing studies of SCZ have uncovered numerous single nucleotide variants (SNVs); however, the majority of these SNVs have unknown functional consequences, leaving their disease relevance uncertain. Filling this knowledge gap requires systematic application of quantitative and scalable assays to assess known and novel biological functions of genes. Here we demonstrate loss-of-function effects of multiple rare coding SNVs found in SCZ subjects in the GIT1 (G protein-coupled receptor kinase interacting ArfGAP 1) gene using functional cell-based assays involving co-expression of GIT1 and PAK3 (p21 protein (Cdc42/Rac)-activated kinase 3). Most notably, a GIT1-R283W variant reported in four independent SCZ cases was defective in activating PAK3 as well as MAPK (Mitogen-activated protein kinase). Similar functional deficits were found for a de novo SCZ variant GIT1-S601N. Additional assays revealed deficits in GIT1-R283W’s capacity to stimulate PAK phosphorylation in cultured hippocampal neurons. Also, GIT1-R283W showed deficits in the induction of GAD1 (Glutamate decarboxylase 1) protein expression. Extending these functional assays to ten additional rare GIT1 variants revealed the existence of an allelic series with the majority of the SCZ case variants exhibiting loss-of-function towards MAPK activation in a manner correlated with loss of PAK3 activation. Taken together, we propose that rare variants in GIT1, along with other genetic and environmental factors, cause dysregulation of PAK3 leading to synaptic deficits in SCZ.

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Section: Discussionmentioning

confidence: 99%

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1–PAK3 signaling in neuroplasticity

et al. 2016

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“…Intronic variants are increasingly recognized as a critical diseasecausing genetic constituent. Several large GWAS have associated intronic SNPs with hearing impairment, 44 bipolar disorder, 45 asthma, 46 and rheumatoid arthritis. 47 A recent report also associates an intronic SNP with serum level of transferrin.…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

Campos

Sun

et al. 2011

Blood

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IntroductionThe von Willebrand factor (VWF) is an essential component of hemostasis at sites of vascular injury. This hemostatically active adhesion ligand also plays a critical role in thrombus formation at the site of a ruptured atherosclerotic plaque and in platelet aggregation induced by high fluid shear stress in areas of severe vascular stenosis. The former results in myocardial infarction when it occurs in coronary arteries, whereas the latter is a major cause of thromboembolism associated with ischemic stroke. 1 VWF is the largest multimeric glycoprotein in the plasma. It is exclusively synthesized in endothelial cells and megakaryocytes initially as a monomeric glycoprotein. In the endoplasmic reticulum and Golgi apparatus of these cells, the monomers form C-terminal disulfide-linked dimers. A various number of dimers subsequently form multimers through N-terminal disulfide linkages, a process assisted by the proteolytic release of a 714-amino acid propeptide. 2,3 The newly synthesized VWF multimers are either constitutively released into the circulation or stored in the Weibel-Palade bodies of endothelial cells and ␣-granules of megakaryocytes/platelets. 4,5 On stimulation, these granules secrete the stored VWF multimers that are rich in ultra-large and hemostatically hyperactive forms. 4,6 Ultra-large VWF multimers are also secreted under endothelial stress caused by inflammation but are rapidly and partially cleaved by the zinc metalloprotease AD-AMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats) into smaller, variable-sized multimers. 7-9 The hemostatic activity of VWF multimers is determined not only by multimer size, 4,10 but also by the quantity of VWF antigen in the circulation. The plasma level of VWF multimers is determined by a dynamic balance between the rate of production and that of clearance. Although acquired conditions are known to affect synthesis and secretion, 11 genetic factors play a major role in regulating VWF synthesis and clearance. It has been reported that genetic factors are responsible for up to 66% of variation in plasma VWF antigen level, of which 30% is related to ABO blood type. 12,13 The human VWF gene is located on chromosome 12. 14,15 It spans approximately 180 kb of nucleotides and contains 52 exons that encode a multidomain prepolypeptide of 2791 amino acids. [14][15][16] The VWF gene is highly polymorphic. 17 Single nucleotide polymorphisms (SNPs) of the coding and promoter sequences in the VWF gene have been extensively studied and found to influence the levels of VWF in the circulation. Furthermore, as a heavily glycosylated polypeptide, 16,18 the level of circulating VWF is also affected by the structure of its carbohydrate side chains, which are associated with ABO blood group, primarily because of the presence or absence of a functional glycosyltransferase that adds either a N-acetylgalactosamine or a D-galactose to a D-galactose side chain on the H antigen. 19 This structural variation in glycosylation has been reported to directly...

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“…A larger series of replication samples did not support this association but an exploratory analysis of the subset of samples most similar to the discovery sample yielded nearly significant association for a non-synonymous PCLO SNP (rs2522833). Although subsequent candidate gene studies have implicated this or other PCLO SNPs in depression (Hek et al, 2010;Minelli et al, 2012), bipolar disorder (Choi et al, 2011), and HPA axis function (Kuehner et al, 2011;Schuhmacher et al, 2011), the gene has not shown association in independent GWAS of MDD. A subsequent GWAS (Kohli et al, 2011) reported a significant recessive association for an SNP (rs1545843) in SLC6A15, a gene involved in transporting neutral amino acids.…”

Section: Common Genetic Variationmentioning

confidence: 99%

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

Smoller

2015

Neuropsychopharmacol

376

243

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Research into the causes of psychopathology has largely focused on two broad etiologic factors: genetic vulnerability and environmental stressors. An important role for familial/heritable factors in the etiology of a broad range of psychiatric disorders was established well before the modern era of genomic research. This review focuses on the genetic basis of three disorder categories-posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and the anxiety disorders-for which environmental stressors and stress responses are understood to be central to pathogenesis. Each of these disorders aggregates in families and is moderately heritable. More recently, molecular genetic approaches, including genome-wide studies of genetic variation, have been applied to identify specific risk variants. In this review, I summarize evidence for genetic contributions to PTSD, MDD, and the anxiety disorders including genetic epidemiology, the role of common genetic variation, the role of rare and structural variation, and the role of gene-environment interaction. Available data suggest that stress-related disorders are highly complex and polygenic and, despite substantial progress in other areas of psychiatric genetics, few risk loci have been identified for these disorders. Progress in this area will likely require analysis of much larger sample sizes than have been reported to date. The phenotypic complexity and genetic overlap among these disorders present further challenges. The review concludes with a discussion of prospects for clinical translation of genetic findings and future directions for research.

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Gene Expression and Genetic Variation Data Implicate PCLO in Bipolar Disorder

Cited by 57 publications

References 54 publications

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1–PAK3 signaling in neuroplasticity

Functional analysis of rare variants found in schizophrenia implicates a critical role for GIT1–PAK3 signaling in neuroplasticity

Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort

The Genetics of Stress-Related Disorders: PTSD, Depression, and Anxiety Disorders

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