Tests of linkage and allelic association between markers in the 1p36 PRKCZ (Protein Kinase C Zeta) gene region and bipolar affective disorder

Kandaswamy, Radhika; McQuillin, Andrew; Curtis, David; Gurling, Hugh

doi:10.1002/ajmg.b.32014

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…Genetic studies have also implicated PKC in BD [141,142,143]. In the following section, we will briefly discuss putative gene candidates involving activator protein 1 (AP-1), GSK-3beta, DAG kinase eta (DGKeta), and PKC interacting protein/histidine triad nucleotide binding protein 1 (PKCI/HINT1), that highlight putative genetic mechanisms underlying BD.…”

Section: Geneticsmentioning

confidence: 99%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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Bipolar disorder (BD) is a major health problem. It causes significant morbidity and imposes a burden on the society. Available treatments help a substantial proportion of patients but are not beneficial for an estimated 40-50%. Thus, there is a great need to further our understanding the pathophysiology of BD to identify new therapeutic avenues. The preponderance of evidence pointed towards a role of protein kinase C (PKC) in BD. We reviewed the literature pertinent to the role of PKC in BD. We present recent advances from preclinical and clinical studies that further support the role of PKC. Moreover, we discuss the role of PKC on synaptogenesis and neuroplasticity in the context of BD. The recent development of animal models of BD, such as stimulant-treated and paradoxical sleep deprivation, and the ability to intervene pharmacologically provide further insights into the involvement of PKC in BD. In addition, the effect of PKC inhibitors, such as tamoxifen, in the resolution of manic symptoms in patients with BD further points in that direction. Furthermore, a wide variety of growth factors influence neurotransmission through several molecular pathways that involve downstream effects of PKC. Our current understanding identifies the PKC pathway as a potential therapeutic avenue for BD.

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Section: Geneticsmentioning

confidence: 99%

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

et al. 2017

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“…4 .B. These regions include the following cytobands: murine 4qE, homologous to human 1p36, implicated in BPD in two studies with linkage scores of 3.97 [60] and 3.1 [61] and a region in which SNPs predict BPD susceptibility [62] ; murine 5qF, homologous to human 12q24, implicated in BPD in multiple studies with linkage scores of 4.91 [63] , 3.63 [64] , 3.37 [65] , 2.8 [61] , and 2.08 [66] and a region in which SNPs and allele variants predict BPD susceptibility [44] , [46] , [67] ; 8qE1, homologous to human 16q24, implicated in BPD in two studies with linkage scores of 3.51 [68] and 2.29 [69] ; murine 11qE2, homologous to human 17q25, implicated in BPD in five studies with linkage scores of 3.11 [70] , 2.4 [71] , 2.4 [72] , 2.1 [73] , and 2.08 [74] ; murine 13qA3 and 17qA3-17qB1, two cytobands with homology to human 6p21–22, implicated in BPD in multiple studies with linkage scores of 3.19 [68] , 2.60 [75] , 2.26 [72] , and 1.91 [69] ; murine 14qA1, homologous to human 3p14, implicated in BPD in two studies with linkage scores of 3.51 [76] and 2.31 [77] ; and murine 16qB2–B3, homologous to human 3q29, implicated in BPD in two studies with linkage scores of 3.74 [78] and 2.0 [61] . Additional enriched genome regions showing weaker previous relationships to BPD included: murine 2qE, homologous to human 11p13, implicated in BPD in one study with a linkage score of 1.95 [79] and a region in which SNPs and allele variants predict BPD susceptibility [80] , [81] ; murine 8qB2–B3.1, homologous to human 4q34, implicated in BPD in a study with a linkage score of 3.28 [82] ; murine 8qB3.3 and 9qA3, homologous to human 19p13, implicated in BPD in three studies with linkage scores of 2.37 [83] , 1.8 [66] , and 1.55 [84] ; and 15qE3, homologous to 22q13, implicated in BPD in o...…”

Section: Resultsmentioning

confidence: 99%

A New Mouse Model for Mania Shares Genetic Correlates with Human Bipolar Disorder

2012

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Bipolar disorder (BPD) is a debilitating heritable psychiatric disorder. Contemporary rodent models for the manic pole of BPD have primarily utilized either single locus transgenics or treatment with psychostimulants. Our lab recently characterized a mouse strain termed Madison (MSN) that naturally displays a manic phenotype, exhibiting elevated locomotor activity, increased sexual behavior, and higher forced swimming relative to control strains. Lithium chloride and olanzapine treatments attenuate this phenotype. In this study, we replicated our locomotor activity experiment, showing that MSN mice display generationally-stable mania relative to their outbred ancestral strain, hsd:ICR (ICR). We then performed a gene expression microarray experiment to compare hippocampus of MSN and ICR mice. We found dysregulation of multiple transcripts whose human orthologs are associated with BPD and other psychiatric disorders including schizophrenia and ADHD, including: Epor, Smarca4, Cmklr1, Cat, Tac1, Npsr1, Fhit, and P2rx7. RT-qPCR confirmed dysregulation for all of seven transcripts tested. Using a novel genome enrichment algorithm, we found enrichment in genome regions homologous to human loci implicated in BPD in replicated linkage studies including homologs of human cytobands 1p36, 3p14, 3q29, 6p21–22, 12q24, 16q24, and 17q25. Using a functional network analysis, we found dysregulation of a gene system related to chromatin packaging, a result convergent with recent human findings on BPD. Our findings suggest that MSN mice represent a polygenic model for the manic pole of BPD showing much of the genetic systems complexity of the corresponding human disorder. Further, the high degree of convergence between our findings and the human literature on BPD brings up novel questions about evolution by analogy in mammalian genomes.

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“…PRKCZ in cord blood T cells has been associated with allergy risk in infants and it has been reported that gender differences affect susceptibility to the development of hypersensitivity reactions [ 33 , 34 ]. The PRKCZ gene has also been linked to development of bipolar disorder [ 35 ] in line with the increased risk of psychiatric illness such as bipolar disorder in males compared to females [ 36 , 37 ].…”

Section: Discussionmentioning

confidence: 99%

The idiopathic preterm delivery methylation profile in umbilical cord blood DNA

et al. 2015

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BackgroundPreterm delivery is the leading cause of neonatal morbidity and mortality. Two-thirds of preterm deliveries are idiopathic. The initiating molecular mechanisms behind spontaneous preterm delivery are unclear. Umbilical cord blood DNA samples are an easy source of material to study the neonatal state at birth. DNA methylation changes can be exploited as markers to identify spontaneous preterm delivery. To identify methylation differences specific to idiopathic preterm delivery, we assessed genome-wide DNA methylation changes in 24 umbilical cord blood samples (UCB) using the 450 K Illumina methylation array. After quality control, conclusions were based on 11 term and 11 idiopathic preterm born neonates. The differentially methylated positions (DMPs) specific for preterm/term delivery, neonatal sex, use of oxytocin and mode of initiation of labor were calculated by controlling the FDR p value at 0.05.ResultsThe analysis identifies 1855 statistically significant DMPs between preterm and term deliveries of which 508 DMPs are also attributable to clinical variables other than preterm versus term delivery.1347 DMPs are unique to term vs preterm delivery, of which 196 DMPs do not relate to gestational age as such. Pathway analysis indicated enrichment of genes involved in calcium signalling, myometrial contraction and relaxation pathways. The 1151 DMPs that correlate with advancing gestational age (p < 0.05) include 161 DMPs that match with two previously reported studies on UCB methylation.Additionally, 123 neonatal sex specific DMPs, 97 DMPs specific to the induction of labour and 42 DMPs specific to the mode of initiation of labor were also identified.ConclusionThis study identifies 196 DMPs in UCB DNA of neonates which do not relate to gestational age or any other clinical variable recorded and are specific to idiopathic preterm delivery. Furthermore, 161 DMPs from our study overlap with previously reported studies of which a subset is also reported to be differentially methylated at 18 years of age. A DMP on MYL4, encoding myosin light chain 4, is a robust candidate for the identification of idiopathic preterm labour as it is identified by all 3 independent studies.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1915-4) contains supplementary material, which is available to authorized users.

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Tests of linkage and allelic association between markers in the 1p36 PRKCZ (Protein Kinase C Zeta) gene region and bipolar affective disorder

Cited by 10 publications

References 36 publications

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature

A New Mouse Model for Mania Shares Genetic Correlates with Human Bipolar Disorder

The idiopathic preterm delivery methylation profile in umbilical cord blood DNA

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