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2.
Mol Psychiatry ; 24(11): 1641-1654, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31481758

RESUMO

Although the underlying neurobiology of major mental illness (MMI) remains unknown, emerging evidence implicates a role for oligodendrocyte-myelin abnormalities. Here, we took advantage of a large family carrying a balanced t(1;11) translocation, which substantially increases risk of MMI, to undertake both diffusion tensor imaging and cellular studies to evaluate the consequences of the t(1;11) translocation on white matter structural integrity and oligodendrocyte-myelin biology. This translocation disrupts among others the DISC1 gene which plays a crucial role in brain development. We show that translocation-carrying patients display significant disruption of  white matter integrity compared with familial controls. At a cellular level, we observe dysregulation of key pathways controlling oligodendrocyte development and morphogenesis in induced pluripotent stem cell (iPSC) derived case oligodendrocytes. This is associated with reduced proliferation and a stunted morphology in vitro. Further, myelin internodes in a humanized mouse model that recapitulates the human translocation as well as after transplantation of t(1;11) oligodendrocyte progenitors were significantly reduced when  compared with controls. Thus we provide evidence that the t(1;11) translocation has biological effects at both the systems and cellular level that together suggest oligodendrocyte-myelin dysfunction.

3.
J Sci Food Agric ; 99(15): 6944-6953, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31414495

RESUMO

BACKGROUND: Dimethyl sulfide (DMS) is a small sulfur-containing impact odorant, imparting distinctive positive and / or negative characters to food and beverages. In white wine, the presence of DMS at perception threshold is considered to be a fault, contributing strong odors reminiscent of asparagus, cooked cabbage, and creamed corn. The source of DMS in wine has long been associated with S-methyl-l-methionine (SMM), a derivative of the amino acid methionine, which is thought to break down into DMS through chemical degradation, particularly during wine ageing. RESULTS: We developed and validated a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with a stable isotope dilution assay (SIDA) to measure SMM in grape juice and wine. The application of this new method for quantitating SMM, followed by the quantitation of DMS using headspace-solid phase micro-extraction coupled with gas chromatography-mass spectrometry (HS-SPME/GC-MS), confirmed that DMS can be produced in wine via the chemical breakdown of SMM to DMS, with greater degradation observed at 28 °C than at 14 °C. Further investigation into the role of grape juice and yeast strain on DMS formation revealed that the DMS produced from three different Sauvignon blanc grape juices, either from the SMM naturally present or SMM spiked at 50 mmol L-1 , was modulated depending on each of the four strains of Saccharomyces cerevisiae wine yeast used for fermentation. CONCLUSION: This study confirms the existence of a chemical pathway to the formation of DMS and reveals a yeast-mediated mechanism towards the formation of DMS from SMM during alcoholic fermentation. © 2019 Society of Chemical Industry.


Assuntos
Cromatografia Líquida/métodos , Sucos de Frutas e Vegetais/análise , Saccharomyces cerevisiae/metabolismo , Sulfetos/metabolismo , Espectrometria de Massas em Tandem/métodos , Vitamina U/análise , Vitis/química , Fermentação , Frutas/química , Frutas/metabolismo , Frutas/microbiologia , Sucos de Frutas e Vegetais/microbiologia , Odorantes/análise , Sulfetos/análise , Vitamina U/metabolismo , Vitis/metabolismo , Vitis/microbiologia , Vinho/análise
4.
Artigo em Inglês | MEDLINE | ID: mdl-30197049

RESUMO

BACKGROUND: Major depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. METHODS: We used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). RESULTS: We found significantly lower FA in the superior longitudinal fasciculus (ß = -.035, pcorrected = .029) and significantly higher MD in a global measure of thalamic radiations (ß = .029, pcorrected = .021), as well as higher MD in the superior (ß = .034, pcorrected = .039) and inferior (ß = .029, pcorrected = .043) longitudinal fasciculus and in the anterior (ß = .025, pcorrected = .046) and superior (ß = .027, pcorrected = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. CONCLUSIONS: Our findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.

5.
Mol Psychiatry ; 24(2): 294-311, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30401811

RESUMO

The molecular basis of how chromosome 16p13.11 microduplication leads to major psychiatric disorders is unknown. Here we have undertaken brain imaging of patients carrying microduplications in chromosome 16p13.11 and unaffected family controls, in parallel with iPS cell-derived cerebral organoid studies of the same patients. Patient MRI revealed reduced cortical volume, and corresponding iPSC studies showed neural precursor cell (NPC) proliferation abnormalities and reduced organoid size, with the NPCs therein displaying altered planes of cell division. Transcriptomic analyses of NPCs uncovered a deficit in the NFκB p65 pathway, confirmed by proteomics. Moreover, both pharmacological and genetic correction of this deficit rescued the proliferation abnormality. Thus, chromosome 16p13.11 microduplication disturbs the normal programme of NPC proliferation to reduce cortical thickness due to a correctable deficit in the NFκB signalling pathway. This is the first study demonstrating a biologically relevant, potentially ameliorable, signalling pathway underlying chromosome 16p13.11 microduplication syndrome in patient-derived neuronal precursor cells.

6.
Food Chem ; 271: 747-752, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30236740

RESUMO

Sauvignon blanc grapes were exposed to an ultra-violet (UV) light source post-hand harvest (whole bunches) or post-machine harvest. The thiol precursors S-3-(hexan-1-ol)-l-cysteine (Cys-3MH) and S-3-(hexan-1-ol)-l-glutathione (GSH-3MH) were quantified in the juices before and after UV treatment. Results showed that irradiation of the grapes with UV light had little to no effect on the thiol precursors. Wines were fermented from the corresponding juices and 18 aroma compounds were quantified. Differences were found between UV treatments of the wines for 3-mercaptohexanol, hexan-1-ol, ethyl butanoate, ethyl hexanoate, ethyl octanoate and phenylethyl alcohol. However, these changes were not significant (p < 0.05) for both grape media trialled. Future studies involving larger sample sizes and replicate numbers should be completed in order to ascertain any changes in aroma chemistry as a result of UV light application to grapes postharvest.


Assuntos
Irradiação de Alimentos/métodos , Compostos de Sulfidrila/efeitos da radiação , Raios Ultravioleta , Vitis/química , Vinho/análise , Odorantes
7.
J Agric Food Chem ; 66(38): 10053-10066, 2018 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-30175910

RESUMO

The effects of two cluster thinning regimes (low and moderate) with Vitis vinifera cv. Pinot noir, in vineyards located in Central Otago, New Zealand, on wine composition, were studied across three consecutive seasons. There were strong correlations between the extent of cluster thinning and pH and bunch weights, and the concentrations of the C13-norisoprenoids, monoterpenes, fatty acids, cinnamic esters, ß-phenylethyl alcohol, and all polyphenols. The sensory terms herbaceous and acidic consistently received the highest ranking in the control wines without cluster thinning. The thinning treatments produced wines with higher marks in the descriptors fruity, spice, sweet, and body. Cluster thinning also had a measurable effect on timing of harvest, in addition to effects on chemical composition and wine sensory, which demonstrate benefits to wine quality that can be expected with cluster thinning of Pinot noir.


Assuntos
Fenóis/química , Vitis/química , Compostos Orgânicos Voláteis/química , Vinho/análise , Adulto , Feminino , Frutas/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Pessoa de Meia-Idade , Paladar
8.
Transl Psychiatry ; 8(1): 184, 2018 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-30190480

RESUMO

The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers.


Assuntos
Proteínas de Transporte/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Translocação Genética , Animais , Proteínas de Transporte/genética , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Modelos Animais , Transtornos do Humor/genética , Mutação , Proteínas do Tecido Nervoso/genética , Plasticidade Neuronal , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/genética , Análise de Sequência de RNA , Sinapses/metabolismo
9.
Curr Top Behav Neurosci ; 40: 13-43, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30030769

RESUMO

The inception of human-induced pluripotent stem cell (hiPSCs) technology has provided an exciting platform upon which the modelling and treatment of human neurodevelopmental and neuropsychiatric disorders may be expedited. Although the genetic architecture of these disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Animal models of neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders, show limitations in recapitulating the full complexity and heterogeneity of human neurodevelopmental disease states. Indeed, patient-derived hiPSCs offer distinct advantages over classical animal models in the study of human neuropathologies. Here we have discussed the current, relative translational merit of hiPSCs in investigating human neurodevelopmental and neuropsychiatric disorders with a specific emphasis on the utility of such systems to aid in the identification of biomarkers. We have highlighted the promises and pitfalls of reprogramming cell fate for the study of these disorders and provide recommendations for future directions in this field in order to overcome current limitations. Ultimately, this will aid in the development of effective clinical strategies for diverse patient populations affected by these disorders with the aim of also leading to biomarker identification.


Assuntos
Células-Tronco Pluripotentes Induzidas , Neurobiologia , Transtornos do Neurodesenvolvimento , Esquizofrenia , Animais , Diferenciação Celular , Humanos , Transtornos do Neurodesenvolvimento/terapia , Esquizofrenia/terapia
10.
Cell Stem Cell ; 22(5): 609-611, 2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29727672

RESUMO

In this issue of Cell Stem Cell, Sarkar et al. (2018) describe an efficient method for the generation of human hippocampal pyramidal neurons from stem cells. They developed a compelling in vitro model that recapitulates synaptic connectivity within the hippocampus and showed that cells derived from patients with schizophrenia exhibit abnormal electrical activity.


Assuntos
Células-Tronco Pluripotentes , Esquizofrenia , Hipocampo , Humanos , Neurônios , Células Piramidais
11.
Artigo em Inglês | MEDLINE | ID: mdl-29352035

RESUMO

Solid progress has occurred over the last decade in our understanding of the molecular genetic basis of neurodevelopmental disorders, and of schizophrenia and autism in particular. Although the genetic architecture of both disorders is far more complex than previously imagined, many key loci have at last been identified. This has allowed in vivo and in vitro technologies to be refined to model specific high-penetrant genetic loci involved in both disorders. Using the DISC1/NDE1 and CYFIP1/EIF4E loci as exemplars, we explore the opportunities and challenges of using animal models and human-induced pluripotent stem cell technologies to further understand/treat and potentially reverse the worst consequences of these debilitating disorders.This article is part of a discussion meeting issue 'Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.


Assuntos
Transtorno Autístico/genética , Modelos Animais de Doenças , Células-Tronco Pluripotentes Induzidas/fisiologia , Mutação , Esquizofrenia/genética , Animais , Animais Geneticamente Modificados , Humanos , Camundongos
12.
J Chromatogr A ; 1537: 91-98, 2018 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-29352581

RESUMO

Sesquiterpenes are a widespread class of compounds of increasing interest found in grapes and wines, amongst many other natural sources. Due to a lack of standards and the complexity of the mass spectra fragmentation, accurate quantification of these low concentration compounds had not previously been accomplished. The current paper presents a new method for the concurrent quantification of several sesquiterpenes. The multivariate method optimisation is presented. Synthesised isotopic standards were utilised in conjunction with solid phase microextraction (SPME) and gas chromatography-tandem mass spectrometry (GC-MS/MS) to perform a standard isotope dilution assay (SIDA). The method was successfully applied to several grape must samples of four different cultivar. To the best of our knowledge this was the first time some of these sesquiterpenes were quantified in grape.


Assuntos
Análise de Alimentos/métodos , Frutas/química , Sesquiterpenos/análise , Espectrometria de Massas em Tandem , Vitis/química , Cromatografia Gasosa-Espectrometria de Massas , Técnicas de Diluição do Indicador , Isótopos/análise , Microextração em Fase Sólida , Vinho/análise
13.
Nat Genet ; 49(8): 1167-1173, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28650482

RESUMO

By performing a meta-analysis of rare coding variants in whole-exome sequences from 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 family trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare, damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In patients with schizophrenia who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known risk genes for neurodevelopmental disorders, a significant rare variant burden persists in other genes intolerant of loss-of-function variants; although this effect is notably stronger in patients with both schizophrenia and intellectual disability, it is also seen in patients with schizophrenia who do not have intellectual disability. Together, our results show that rare, damaging variants contribute to the risk of schizophrenia both with and without intellectual disability and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.


Assuntos
Predisposição Genética para Doença , Deficiência Intelectual/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Exoma , Variação Genética , Técnicas de Genotipagem , Humanos , Mutação , Transtornos do Neurodesenvolvimento/genética , Polimorfismo de Nucleotídeo Único , Esquizofrenia/fisiopatologia , Análise de Sequência de DNA
14.
Food Chem ; 209: 341-7, 2016 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-27173572

RESUMO

Hydrogen sulfide (H2S) is produced by yeast during winemaking and possesses off-flavors reminiscent of rotten eggs. The production of H2S during fermentation has also been associated in the finished wine with the rise of additional volatile sulfur compounds (VSCs) with strong aromas of cooked onions and vegetables. To characterize these more complex VSCs produced from H2S, we performed fermentations in synthetic grape juice. H2S production was manipulated experimentally by feeding increasing concentrations of sulfate to mutant strains that are unable to incorporate H2S efficiently as part of the sulfur assimilation pathway. In finished wines from these mutants, three VSCs - ethanethiol, S-ethyl thioacetate and diethyl disulfide - increased proportionally to H2S. (34)S-labeled sulfate fed to the MET17-deleted strain was incorporated into same three VSCs, demonstrating that they are formed directly from H2S.


Assuntos
Acetatos/análise , Fermentação , Sulfeto de Hidrogênio/análise , Saccharomyces cerevisiae/metabolismo , Compostos de Sulfidrila/análise , Sulfetos/análise , Vitis/metabolismo , Vinho/análise , Cisteína Sintase/genética , Frutas/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Sulfatos/química
15.
Food Chem ; 208: 326-35, 2016 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-27132857

RESUMO

In the wine industry, fining agents are commonly used with many choices now commercially available. Here the influence of pre-fermentation fining on wine aroma chemistry has been explored. Free run and press fraction Sauvignon blanc juices from two vineyards were fined using gelatin, activated carbon, polyvinylpolypyrrolidone (PVPP) and a combination agent which included bentonite, PVPP and isinglass. Over thirty aroma compounds were quantified in the experimental wines. Results showed that activated carbon fining led to a significant (p<0.05) concentration decrease of hexan-1-ol and linalool in the experimental wines when compared to a control, consistent across all vineyard and fraction combinations. Other aroma compounds were also influenced by fining agent, even if vineyards and press fractions played a crucial role. This study confirmed that fining agents used pre-fermentation can influence wine aroma profiles and therefore needs specific tailoring addressing style and origin of grape.


Assuntos
Fermentação , Aromatizantes/química , Manipulação de Alimentos/métodos , Olfato , Vitis/química , Vinho/análise , Hexanóis/análise , Monoterpenos/análise
16.
Nat Neurosci ; 19(4): 571-7, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26974950

RESUMO

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neuropsychiatric diagnosis, indicating that SETD1A is substantially depleted of LoF variants in the general population. Seven of the ten individuals with schizophrenia carrying SETD1A LoF variants also had learning difficulties. We further identified four SETD1A LoF carriers among 4,281 children with severe developmental disorders and two more carriers in an independent sample of 5,720 Finnish exomes, both with notable neuropsychiatric phenotypes. Together, our observations indicate that LoF variants in SETD1A cause a range of neurodevelopmental disorders, including schizophrenia. Combining these data with previous common variant evidence, we suggest that epigenetic dysregulation, specifically in the histone H3K4 methylation pathway, is an important mechanism in the pathogenesis of schizophrenia.


Assuntos
Estudos de Associação Genética/métodos , Variação Genética/genética , Histona-Lisina N-Metiltransferase/genética , Transtornos do Neurodesenvolvimento/genética , Esquizofrenia/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Finlândia/epidemiologia , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/epidemiologia , Esquizofrenia/diagnóstico , Esquizofrenia/epidemiologia
17.
J Agric Food Chem ; 63(36): 8017-24, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26271945

RESUMO

Volatile sulfur compounds (VSCs) play a significant role in the aroma of foods and beverages. With very low sensory thresholds and strong unpleasant aromas, most VSCs are considered to have a negative impact on wine quality. In this study, headspace solid phase microextraction coupled with gas chromatography-mass spectrometry (HS-SPME/GC-MS) was used to analyze the time course of the biosynthesis of 12 VSCs formed during wine fermentation. Two different strains of Saccharomyces cerevisiae, the laboratory strain BY4743 and a commercial strain, F15, were assessed using two media: synthetic grape media and Sauvignon Blanc juice. Seven VSCs were detected above background, with three rising above their sensory thresholds. The data revealed remarkable differences in the timing and evolution of production during fermentation, with a transient spike in methanethiol production early during anaerobic growth. Heavier VSCs such as benzothiazole and S-ethyl thioacetate were produced at a steady rate throughout grape juice fermentation, whereas others, such as diethyl sulfide, appear toward the very end of the winemaking process. The results also demonstrate significant differences between yeast strains and fermentation media.


Assuntos
Saccharomyces cerevisiae/metabolismo , Compostos de Enxofre/metabolismo , Vinho/análise , Fermentação , Cromatografia Gasosa-Espectrometria de Massas , Odorantes/análise , Compostos de Enxofre/química , Vitis/química , Vitis/metabolismo , Vitis/microbiologia , Vinho/microbiologia
18.
Mol Neuropsychiatry ; 1(3): 175-190, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27239468

RESUMO

Robust statistical, genetic and functional evidence supports a role for DISC1 in the aetiology of major mental illness. Furthermore, many of its protein-binding partners show evidence for involvement in the pathophysiology of a range of neurodevelopmental and psychiatric disorders. Copy number variants (CNVs) are suspected to play an important causal role in these disorders. In this study, CNV analysis of DISC1 and its binding partners PAFAH1B1, NDE1, NDEL1, FEZ1, MAP1A, CIT and PDE4B in Scottish and Northern Swedish population-based samples was carried out using multiplex amplicon quantification. Here, we report the finding of rare CNVs in DISC1, NDE1 (together with adjacent genes within the 16p13.11 duplication), NDEL1 (including the overlapping MYH10 gene) and CIT. Our findings provide further evidence for involvement of DISC1 and its interaction partners in neuropsychiatric disorders and also for a role of structural variants in the aetiology of these devastating diseases.

19.
Curr Psychiatry Rep ; 16(11): 502, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25200985

RESUMO

The genetic basis of schizophrenia has been a hotly debated research topic for decades, yet recent studies, especially in the past year, have confirmed genetics as the major cause of this complex condition. Psychiatry has come of age: it is perhaps more difficult for the current generation of psychiatrists, to comprehend how the biological root of the condition could have been denied for so long. Here we review how highly collaborative global efforts to pool samples, utilise the very latest advances in genotyping and high throughput sequencing technologies, and application of robust statistical analysis have reaped phenomenal rewards. The major findings are that schizophrenia is a highly polygenic disorder with a complex array of risk loci, many include genes implicated also in intellectual disability, autism spectrum disorders, bipolar disorder and major depressive disorder. These candidate genes converge on key neuronal signalling pathways identifying novel targets for potential future therapeutic intervention.


Assuntos
Variação Genética/genética , Herança Multifatorial/genética , Esquizofrenia/genética , Humanos
20.
Hum Mol Genet ; 23(12): 3316-26, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24474471

RESUMO

Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 × 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, ∞]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein-Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 × 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co-expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity.


Assuntos
Transtorno Bipolar/genética , Duplicação Cromossômica , Proteínas do Tecido Nervoso/metabolismo , Transtornos Psicóticos/genética , Esquizofrenia/genética , Quinases Ativadas por p21/genética , Quinases Ativadas por p21/metabolismo , Transtorno Bipolar/patologia , Estudos de Casos e Controles , Pontos de Quebra do Cromossomo , Variações do Número de Cópias de DNA , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Masculino , Plasticidade Neuronal , Transtornos Psicóticos/patologia , Esquizofrenia/patologia
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