Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function

Maycox, Peter R.; Kelly, F. M.; Taylor, Adam; Bates, Stewart; Reid, Juliet L.; Logendra, R; Barnes, Michael R.; Larminie, Christopher; Jones, Nick D.; Lennon, Mark; Davies, Ceri H.; Hagan, Jim J.; Scorer, Carol A.; Angelinetta, Claire; Akbar, Mohammed T.; Hirsch, Steven R.; Mortimer, Ann; Barnes, Thomas R. E.; Belleroche, Jackie de

doi:10.1038/mp.2009.18

Cited by 191 publications

(195 citation statements)

References 55 publications

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“…We analysed data from seven, published, microarray‐based studies of age‐related changes in RNA expression (Barnes et al, 2011; Berchtold et al, 2008; Colantuoni et al, 2011; Kang et al, 2011; Lu et al, 2004; Maycox et al, 2009; Somel et al, 2010, 2011 ). The data came from 22 different brain regions, and the ages of the donors ranged from 20 to 106 years (Figure 1a and Supporting Information Figure S1a).…”

Section: Resultsmentioning

confidence: 99%

Gene expression‐based drug repurposing to target aging

et al. 2018

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Aging is the largest risk factor for a variety of noncommunicable diseases. Model organism studies have shown that genetic and chemical perturbations can extend both lifespan and healthspan. Aging is a complex process, with parallel and interacting mechanisms contributing to its aetiology, posing a challenge for the discovery of new pharmacological candidates to ameliorate its effects. In this study, instead of a target‐centric approach, we adopt a systems level drug repurposing methodology to discover drugs that could combat aging in human brain. Using multiple gene expression data sets from brain tissue, taken from patients of different ages, we first identified the expression changes that characterize aging. Then, we compared these changes in gene expression with drug‐perturbed expression profiles in the Connectivity Map. We thus identified 24 drugs with significantly associated changes. Some of these drugs may function as antiaging drugs by reversing the detrimental changes that occur during aging, others by mimicking the cellular defence mechanisms. The drugs that we identified included significant number of already identified prolongevity drugs, indicating that the method can discover de novo drugs that meliorate aging. The approach has the advantages that using data from human brain aging data, it focuses on processes relevant in human aging and that it is unbiased, making it possible to discover new targets for aging studies.

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Section: Resultsmentioning

confidence: 99%

Gene expression‐based drug repurposing to target aging

et al. 2018

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“…To seek the potential genes that are differentially expressed between schizophrenia patients and healthy controls, many expression microarrays have been performed and numerous dysregulated genes have been identified. [27][28][29][30] However, we noticed that only very limited overlapping genes were identified among different expression studies, which is likely due to the use of different brain regions and quantitative methods. In addition, the quality of the analyzed samples and sample size may also influence the identification of dysregulated genes in individuals with schizophrenia.…”

Section: Introductionmentioning

confidence: 86%

“…To identify genes that are consistently dysregulated (downregulated or upregulated) in the prefrontal cortex of schizophrenia patients from different expression studies, we compared the dysregulated genes from two recent expression studies. 27,30 We found three genes (CAMKK2, CACNB3 and SNN) were consistently downregulated in both expression studies, suggesting these genes are likely high-confidence downregulated genes in schizophrenia patients compared with normal controls. In addition, we also identified two genes (WNK1 and ABCA1) that were consistently upregulated in prefrontal cortex of individuals with schizophrenia in both studies.…”

Section: Introductionmentioning

confidence: 92%

“…We selected two well-characterized genome-wide expression studies 27,30 from recent publications, which were performed in individuals with schizophrenia and their matched controls. The first study measured the expression of over 30 000 mRNA transcripts in postmortem tissue from a brain region associated with the pathophysiology of schizophrenia (Brodmann area 10: anterior prefrontal cortex) in two large schizophrenia cohorts.…”

Section: Expression Data Used In This Studymentioning

confidence: 99%

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Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Luo

Huang

et al. 2013

Mol Psychiatry

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“…Levels of SNAP-25 mRNA have been reported to be increased in the superior temporal cortex of the younger group of schizophrenic patients 79 . A microarray study in the prefrontal cortex showed altered expression of genes associated with synaptic vesicle recycling in schizophrenia 80 . Accordingly, on the protein level reduced synaptophysin and SNAP-25 immunoreactivity have been detected in the prefrontal cortex 60,69,[81][82][83] .…”

Section: Schizophrenia As a Disorder Of Disturbed Synaptic Plasticitymentioning

confidence: 99%

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

Schmitt

Reich‐Erkelenz²,

Gebicke‐Härter

et al. 2012

Arch. Clin. Psychiatry (São Paulo)

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Schizophrenia is a severe neurobiological disease with genetic and environmental factors playing a role in the pathophysiology. Several brain regions have been implicated in the disease process and are connected in complex neuronal circuits. On the cellular and molecular level, affected connectivity between these regions, involving dysfunctional myelination of neuronal axons, as well as alterations on the synaptic level and energy metabolism of neurons leading to disturbances in synaptic plasticity are major findings in post-mortem studies. Microarray studies investigating genome-wide gene expression have contributed to the findings of alterations in complex pathways in relevant brain regions in schizophrenia. Moreover, first laser-capture microdissection studies allowed the investigation of gene expression in specific groups of neurons. However, it must be kept in mind that in post-mortem studies confounding effects of medication, mRNA quality as well as the capability of the brain for neuroplastic regenerative mechanisms in individuals with a lifetime history of schizophrenia may influence the complex pattern of alterations on the molecular level. Despite these limitations, hypothesis-free transcriptome studies in brain tissue from schizophrenia patients offer a unique possibility to learn more about underlying mechanisms, leading to new insights in the pathophysiology of the disease. A, et al. / Rev Psiq Clín. 2013;40(1):10-5 Keywords: Schizophrenia, gene expression, microarray, RT-PCR, in situ hybridization, brain regions. Schmitt ResumoEsquizofrenia é uma severa doença neurobiológica com fatores genéticos e ambientais desempenhando um papel na fisiopatologia. Diversas regiões cerebrais têm sido implicadas no processo da doença e estão conectadas em complexos circuitos neuronais. Nos níveis molecular e celular, a conectividade afetada entre essas regiões, envolvendo mielinização disfuncional dos axônios neuronais, bem como as alterações no nível sináptico e metabolismo energético levando a distúrbios na plasticidade sináptica, são os maiores achados em estudos post-mortem. Estudos de microarranjos investigando a expressão gênica contribuíram para os achados de alterações em vias complexas em regiões cerebrais relevantes na esquizofrenia. Além disso, estudos utilizando microdissecção e captura a laser permitiram a investigação da expressão gênica em grupos específicos de neurônios. Entretanto, deve ser mantido em mente que em estudos post-mortem, confusos efeitos de medicação, qualidade de RNAm, bem como capacidade de mecanismos regenerativos neuroplásticos do cérebro em indivíduos com história de vida de esquizofrenia, podem influenciar o complexo padrão de alterações no nível molecular. Apesar dessas limitações, estudos transcriptômicos livres de hipóteses em tecido cerebral de pacientes esquizofrênicos oferecem uma possibilidade única para aprender mais sobre os mecanismos subjacentes, levando a novas ópticas da fisiopatologia da doença. A, et al. / Rev Psiq Clín. 2013;40(1):10-5 Palavras-cha...

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Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function

Cited by 191 publications

References 55 publications

Gene expression‐based drug repurposing to target aging

Gene expression‐based drug repurposing to target aging

Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Estudos transcriptômicos no contexto da conectividade perturbada em esquizofrenia

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