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Article ; Online: From Schizophrenia Genetics to Disease Biology: Harnessing New Concepts and Technologies.

Duan, Jubao / Sanders, Alan R / Gejman, Pablo V

Journal of psychiatry and brain science

2019 Volume 4

Abstract: Schizophrenia (SZ) is a severe mental disorder afflicting around 1% of the population. It is highly heritable but with complex genetics. Recent research has unraveled a plethora of risk loci for SZ. Accordingly, our conceptual understanding of SZ ... ...

Abstract	Schizophrenia (SZ) is a severe mental disorder afflicting around 1% of the population. It is highly heritable but with complex genetics. Recent research has unraveled a plethora of risk loci for SZ. Accordingly, our conceptual understanding of SZ genetics has been rapidly evolving, from oligogenic models towards polygenic or even omnigenic models. A pressing challenge to the field, however, is the translation of the many genetic findings of SZ into disease biology insights leading to more effective treatments. Bridging this gap requires the integration of genetic findings and functional genomics using appropriate cellular models. Harnessing new technologies, such as the development of human induced pluripotent stem cells (hiPSC) and the CRISPR/Cas-based genome/epigenome editing approach are expected to change our understanding of SZ disease biology to a fundamentally higher level. Here, we discuss some new developments.
Language	English
Publishing date	2019-09-19
Publishing country	England
Document type	Journal Article
ISSN	2398-385X
ISSN (online)	2398-385X
DOI	10.20900/jpbs.20190014
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Article: Clinotator: analyzing ClinVar variation reports to prioritize reclassification efforts.

Butler Iii, Robert R / Gejman, Pablo V

F1000Research

2018 Volume 7, Page(s) 462

Abstract: While ClinVar has become an indispensable resource for clinical variant interpretation, its sophisticated structure provides it with a daunting learning curve. Often the sheer depth of types of information provided can make it difficult to analyze ... ...

Abstract	While ClinVar has become an indispensable resource for clinical variant interpretation, its sophisticated structure provides it with a daunting learning curve. Often the sheer depth of types of information provided can make it difficult to analyze variant information with high throughput. Clinotator is a fast and lightweight tool to extract important aspects of criteria-based clinical assertions; it uses that information to generate several metrics to assess the strength and consistency of the evidence supporting the variant clinical significance. Clinical assertions are weighted by significance type, age of submission and submitter expertise category to filter outdated or incomplete assertions that otherwise confound interpretation. This can be accomplished in batches: either lists of Variation IDs or dbSNP rsIDs, or with vcf files that are additionally annotated. Using sample sets ranging from 15,000-50,000 variants, we slice out problem variants in minutes without extensive computational effort (using only a personal computer) and corroborate recently reported trends of discordance hiding amongst the curated masses. With the rapidly growing body of variant evidence, most submitters and researchers have limited resources to devote to variant curation. Clinotator provides efficient, systematic prioritization of discordant variants in need of reclassification. The hope is that this tool can inform ClinVar curation and encourage submitters to keep their clinical assertions current by focusing their efforts. Additionally, researchers can utilize new metrics to analyze variants of interest in pursuit of new insights into pathogenicity.
Language	English
Publishing date	2018-04-13
Publishing country	England
Document type	Journal Article
ZDB-ID	2699932-8
ISSN	2046-1402
ISSN	2046-1402
DOI	10.12688/f1000research.14470.2
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Article ; Online: From Schizophrenia Genetics to Disease Biology

Jubao Duan / Alan R. Sanders / Pablo V. Gejman

Journal of Psychiatry and Brain Science (2019)

Harnessing New Concepts and Technologies

2019

Abstract	Schizophrenia (SZ) is a severe mental disorder afflicting around 1% of the population. It is highly heritable but with complex genetics. Recent research has unraveled a plethora of risk loci for SZ. Accordingly, our conceptual understanding of SZ genetics has been rapidly evolving, from oligogenic models towards polygenic or even omnigenic models. A pressing challenge to the field, however, is the translation of the many genetic findings of SZ into disease biology insights leading to more effective treatments. Bridging this gap requires the integration of genetic findings and functional genomics using appropriate cellular models. Harnessing new technologies, such as the development of human induced pluripotent stem cells (hiPSC) and the CRISPR/Cas-based genome/epigenome editing approach are expected to change our understanding of SZ disease biology to a fundamentally higher level. Here, we discuss some new developments.
Keywords	schizophrenia ; genetics ; genome-wide association study ; functional genomics ; epigenomics ; chromatin modification ; model organism ; human induced pluripotent stem cells (hiPSCs) ; genome editing ; Medicine ; R
Language	English
Publishing date	2019-09-01T00:00:00Z
Publisher	Hapres Limited
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Clinotator

Robert R. Butler III / Pablo V. Gejman

F1000Research, Vol

analyzing ClinVar variation reports to prioritize reclassification efforts [version 1; referees: 2 approved]

2018 Volume 7

Abstract	While ClinVar has become an indispensable resource for clinical variant interpretation, its sophisticated structure provides it with a daunting learning curve. Often the sheer depth of types of information provided can make it difficult to analyze variant information with high throughput. Clinotator is a fast and lightweight tool to extract important aspects of criteria-based clinical assertions; it uses that information to generate several metrics to assess the strength and consistency of the evidence supporting the variant clinical significance. Clinical assertions are weighted by significance type, age of submission and submitter expertise category to filter outdated or incomplete assertions that otherwise confound interpretation. This can be accomplished in batches: either lists of Variation IDs or dbSNP rsIDs, or with vcf files that are additionally annotated. Using sample sets ranging from 15,000–50,000 variants, we slice out problem variants in minutes without extensive computational effort (using only a personal computer) and corroborate recently reported trends of discordance hiding amongst the curated masses. With the rapidly growing body of variant evidence, most submitters and researchers have limited resources to devote to variant curation. Clinotator provides efficient, systematic prioritization of discordant variants in need of reclassification. The hope is that this tool can inform ClinVar curation and encourage submitters to keep their clinical assertions current by focusing their efforts. Additionally, researchers can utilize new metrics to analyze variants of interest in pursuit of new insights into pathogenicity.
Keywords	Medicine ; R ; Science ; Q
Subject code	020
Language	English
Publishing date	2018-04-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
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Article ; Online: Clinotator

Robert R. Butler III / Pablo V. Gejman

F1000Research, Vol

analyzing ClinVar variation reports to prioritize reclassification efforts [version 2; referees: 2 approved]

2018 Volume 7

Abstract	While ClinVar has become an indispensable resource for clinical variant interpretation, its sophisticated structure provides it with a daunting learning curve. Often the sheer depth of types of information provided can make it difficult to analyze variant information with high throughput. Clinotator is a fast and lightweight tool to extract important aspects of criteria-based clinical assertions; it uses that information to generate several metrics to assess the strength and consistency of the evidence supporting the variant clinical significance. Clinical assertions are weighted by significance type, age of submission and submitter expertise category to filter outdated or incomplete assertions that otherwise confound interpretation. This can be accomplished in batches: either lists of Variation IDs or dbSNP rsIDs, or with vcf files that are additionally annotated. Using sample sets ranging from 15,000–50,000 variants, we slice out problem variants in minutes without extensive computational effort (using only a personal computer) and corroborate recently reported trends of discordance hiding amongst the curated masses. With the rapidly growing body of variant evidence, most submitters and researchers have limited resources to devote to variant curation. Clinotator provides efficient, systematic prioritization of discordant variants in need of reclassification. The hope is that this tool can inform ClinVar curation and encourage submitters to keep their clinical assertions current by focusing their efforts. Additionally, researchers can utilize new metrics to analyze variants of interest in pursuit of new insights into pathogenicity.
Keywords	Medicine ; R ; Science ; Q
Subject code	020
Language	English
Publishing date	2018-06-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: La etiología de la esquizofrenia.

Gejman, Pablo V / Sanders, Alan R

Medicina

2012 Volume 72, Issue 3, Page(s) 227–234

Abstract: Research conducted in recent years represents a new dawn of knowledge for the risk factors of schizophrenia, and genome-wide approaches have revolutionized the field of genetic mapping of schizophrenia. The aggregate genetic data increasingly support a ... ...

Title translation	The etiology of schizophrenia.
Abstract	Research conducted in recent years represents a new dawn of knowledge for the risk factors of schizophrenia, and genome-wide approaches have revolutionized the field of genetic mapping of schizophrenia. The aggregate genetic data increasingly support a combination of rare and common genetic variation in schizophrenia, a major role for polygenic inheritance, and a genetic overlap (pleiotropy) of schizophrenia and other psychiatric disorders, such as bipolar disorder and autism. A main challenge for the field is the translation of established genetic associations into a better pathophysiological understanding of schizophrenia. The current and upcoming resequencing programs - both exomes (all exons) and full genomes - and genome-wide transcriptional analyses will allow a more thorough dissection of the molecular genetics of the disorder.
MeSH term(s)	Autistic Disorder/genetics ; Bipolar Disorder/genetics ; DNA Copy Number Variations ; Genome-Wide Association Study ; Humans ; Polymorphism, Single Nucleotide ; Risk Factors ; Schizophrenia/genetics
Language	Spanish
Publishing date	2012
Publishing country	Argentina
Document type	English Abstract ; Journal Article ; Review
ZDB-ID	411586-7
ISSN	1669-9106 ; 0025-7680 ; 0325-951X
ISSN (online)	1669-9106
ISSN	0025-7680 ; 0325-951X
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Zs.B 163: Show issues

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Article ; Online: Loss of function of OTUD7A in the schizophrenia- associated 15q13.3 deletion impairs synapse development and function in human neurons.

Kozlova, Alena / Zhang, Siwei / Kotlar, Alex V / Jamison, Brendan / Zhang, Hanwen / Shi, Serena / Forrest, Marc P / McDaid, John / Cutler, David J / Epstein, Michael P / Zwick, Michael E / Pang, Zhiping P / Sanders, Alan R / Warren, Stephen T / Gejman, Pablo V / Mulle, Jennifer G / Duan, Jubao

American journal of human genetics

2022 Volume 109, Issue 8, Page(s) 1500–1519

Abstract: Identifying causative gene(s) within disease-associated large genomic regions of copy-number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we ... ...

Abstract	Identifying causative gene(s) within disease-associated large genomic regions of copy-number variants (CNVs) is challenging. Here, by targeted sequencing of genes within schizophrenia (SZ)-associated CNVs in 1,779 SZ cases and 1,418 controls, we identified three rare putative loss-of-function (LoF) mutations in OTU deubiquitinase 7A (OTUD7A) within the 15q13.3 deletion in cases but none in controls. To tie OTUD7A LoF with any SZ-relevant cellular phenotypes, we modeled the OTUD7A LoF mutation, rs757148409, in human induced pluripotent stem cell (hiPSC)-derived induced excitatory neurons (iNs) by CRISPR-Cas9 engineering. The mutant iNs showed a ∼50% decrease in OTUD7A expression without undergoing nonsense-mediated mRNA decay. The mutant iNs also exhibited marked reduction of dendritic complexity, density of synaptic proteins GluA1 and PSD-95, and neuronal network activity. Congruent with the neuronal phenotypes in mutant iNs, our transcriptomic analysis showed that the set of OTUD7A LoF-downregulated genes was enriched for those relating to synapse development and function and was associated with SZ and other neuropsychiatric disorders. These results suggest that OTUD7A LoF impairs synapse development and neuronal function in human neurons, providing mechanistic insight into the possible role of OTUD7A in driving neuropsychiatric phenotypes associated with the 15q13.3 deletion.
MeSH term(s)	DNA Copy Number Variations ; Humans ; Induced Pluripotent Stem Cells ; Neurons ; Schizophrenia/metabolism ; Synapses/metabolism
Language	English
Publishing date	2022-06-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	219384-x
ISSN	1537-6605 ; 0002-9297
ISSN (online)	1537-6605
ISSN	0002-9297
DOI	10.1016/j.ajhg.2022.07.001
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Zs.A 107: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
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Article ; Online: Dopamine perturbation of gene co-expression networks reveals differential response in schizophrenia for translational machinery.

Kos, Mark Z / Duan, Jubao / Sanders, Alan R / Blondell, Lucy / Drigalenko, Eugene I / Carless, Melanie A / Gejman, Pablo V / Göring, Harald H H

Translational psychiatry

2018 Volume 8, Issue 1, Page(s) 278

Abstract: The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various ... ...

Abstract	The dopaminergic hypothesis of schizophrenia (SZ) postulates that positive symptoms of SZ, in particular psychosis, are due to disturbed neurotransmission via the dopamine (DA) receptor D2 (DRD2). However, DA is a reactive molecule that yields various oxidative species, and thus has important non-receptor-mediated effects, with empirical evidence of cellular toxicity and neurodegeneration. Here we examine non-receptor-mediated effects of DA on gene co-expression networks and its potential role in SZ pathology. Transcriptomic profiles were measured by RNA-seq in B-cell transformed lymphoblastoid cell lines from 514 SZ cases and 690 controls, both before and after exposure to DA ex vivo (100 μM). Gene co-expression modules were identified using Weighted Gene Co-expression Network Analysis for both baseline and DA-stimulated conditions, with each module characterized for biological function and tested for association with SZ status and SNPs from a genome-wide panel. We identified seven co-expression modules under baseline, of which six were preserved in DA-stimulated data. One module shows significantly increased association with SZ after DA perturbation (baseline: P = 0.023; DA-stimulated: P = 7.8 × 10
MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cell Line ; Dopamine/administration & dosage ; Dopamine/metabolism ; Female ; Gene Expression Regulation ; Gene Regulatory Networks ; Genome-Wide Association Study ; Humans ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; Quantitative Trait Loci ; Schizophrenia/genetics ; Schizophrenia/metabolism ; Sequence Analysis, RNA ; Transcriptome ; Young Adult
Chemical Substances	Dopamine (VTD58H1Z2X)
Language	English
Publishing date	2018-12-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2609311-X
ISSN	2158-3188 ; 2158-3188
ISSN (online)	2158-3188
ISSN	2158-3188
DOI	10.1038/s41398-018-0325-1
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Article ; Online: Excitatory Dysfunction Drives Network and Calcium Handling Deficits in 16p11.2 Duplication Schizophrenia Induced Pluripotent Stem Cell-Derived Neurons.

Parnell, Euan / Culotta, Lorenza / Forrest, Marc P / Jalloul, Hiba A / Eckman, Blair L / Loizzo, Daniel D / Horan, Katherine K E / Dos Santos, Marc / Piguel, Nicolas H / Tai, Derek J C / Zhang, Hanwen / Gertler, Tracy S / Simkin, Dina / Sanders, Alan R / Talkowski, Michael E / Gejman, Pablo V / Kiskinis, Evangelos / Duan, Jubao / Penzes, Peter

Biological psychiatry

2022 Volume 94, Issue 2, Page(s) 153–163

Abstract: Background: Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell- ... ...

Abstract	Background: Schizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold. Methods: To dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures. Results: In iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation. Conclusions: Our results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant.
MeSH term(s)	Humans ; Schizophrenia/genetics ; Schizophrenia/pathology ; Induced Pluripotent Stem Cells ; Calcium ; Neurons/pathology
Chemical Substances	Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-11-09
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209434-4
ISSN	1873-2402 ; 0006-3223
ISSN (online)	1873-2402
ISSN	0006-3223
DOI	10.1016/j.biopsych.2022.11.005
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Zs.A 720: Show issues

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Article ; Online: Genetics of schizophrenia: new findings and challenges.

Gejman, Pablo V / Sanders, Alan R / Kendler, Kenneth S

Annual review of genomics and human genetics

2011 Volume 12, Page(s) 121–144

Abstract: The work conducted using genome-wide approaches during the past several years has invigorated the field, and represents the dawn of molecular genetics of schizophrenia. The aggregate data increasingly support a combination of rare and common genetic ... ...

Abstract	The work conducted using genome-wide approaches during the past several years has invigorated the field, and represents the dawn of molecular genetics of schizophrenia. The aggregate data increasingly support a combination of rare and common genetic variation in schizophrenia, a major role for polygenic inheritance, and a genetic overlap of schizophrenia and other psychiatric disorders, such as bipolar disorder and autism. The current and upcoming resequencing programs (full exomes to full genomes), in combination with the use of more informative genotyping arrays, will allow a more thorough dissection of the molecular genetics of the disorder. A main challenge for the field is the translation of established genetic associations into a better pathophysiological understanding of schizophrenia.
MeSH term(s)	Adoption ; Genetic Pleiotropy ; Genome-Wide Association Study ; Humans ; Mental Disorders/genetics ; Schizophrenia/genetics ; Twin Studies as Topic
Language	English
Publishing date	2011
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2037670-4
ISSN	1545-293X ; 1527-8204
ISSN (online)	1545-293X
ISSN	1527-8204
DOI	10.1146/annurev-genom-082410-101459
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