20 results on '"Culley, Oliver J."'
Search Results
2. Common genetic variation drives molecular heterogeneity in human iPSCs
- Author
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Kilpinen, Helena, Goncalves, Angela, Leha, Andreas, Afzal, Vackar, Alasoo, Kaur, Ashford, Sofie, Bala, Sendu, Bensaddek, Dalila, Casale, Francesco Paolo, Culley, Oliver J., Danecek, Petr, Faulconbridge, Adam, Harrison, Peter W., Kathuria, Annie, McCarthy, Davis, McCarthy, Shane A., Meleckyte, Ruta, Memari, Yasin, Moens, Nathalie, Soares, Filipa, Mann, Alice, Streeter, Ian, Agu, Chukwuma A., Alderton, Alex, Nelson, Rachel, Harper, Sarah, Patel, Minal, White, Alistair, Patel, Sharad R., Clarke, Laura, Halai, Reena, Kirton, Christopher M., Kolb-Kokocinski, Anja, Beales, Philip, Birney, Ewan, Danovi, Davide, Lamond, Angus I., Ouwehand, Willem H., Vallier, Ludovic, Watt, Fiona M., Durbin, Richard, Stegle, Oliver, and Gaffney, Daniel J.
- Subjects
Genetic variation -- Health aspects ,Stem cells -- Genetic aspects -- Health aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 546% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells., Author(s): Helena Kilpinen [1]; Angela Goncalves [2]; Andreas Leha [2]; Vackar Afzal [3]; Kaur Alasoo [2]; Sofie Ashford [4]; Sendu Bala [2]; Dalila Bensaddek [3]; Francesco Paolo Casale [1]; Oliver [...]
- Published
- 2017
- Full Text
- View/download PDF
3. Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease
- Author
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Belbin, Olivia, Carrasquillo, Minerva M., Crump, Michael, Culley, Oliver J., Hunter, Talisha A., Ma, Li, Bisceglio, Gina, Zou, Fanggeng, Allen, Mariet, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Morgan, Kevin, and Younkin, Steven G.
- Published
- 2011
- Full Text
- View/download PDF
4. Differential Expression of Insulin-Like Growth Factor 1 and Wnt Family Member 4 Correlates With Functional Heterogeneity of Human Dermal Fibroblasts
- Author
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Culley, Oliver J., primary, Louis, Blaise, additional, Philippeos, Christina, additional, Oulès, Bénédicte, additional, Tihy, Matthieu, additional, Segal, Joe M., additional, Hyliands, Della, additional, Jenkins, Gail, additional, Bhogal, Ranjit K., additional, Siow, Richard C., additional, and Watt, Fiona M., additional
- Published
- 2021
- Full Text
- View/download PDF
5. Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs
- Author
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Kilpinen, Helena, Goncalves, Angela, Leha, Andreas, Afzal, Vackar, Alasoo, Kaur, Ashford, Sofie, Bala, Sendu, Bensaddek, Dalila, Casale, Francesco Paolo, Culley, Oliver J., Danecek, Petr, Faulconbridge, Adam, Harrison, Peter W., Kathuria, Annie, McCarthy, Davis, McCarthy, Shane A., Meleckyte, Ruta, Memari, Yasin, Moens, Nathalie, Soares, Filipa, Mann, Alice, Streeter, Ian, Agu, Chukwuma A., Alderton, Alex, Nelson, Rachel, Harper, Sarah, Patel, Minal, White, Alistair, Patel, Sharad R., Clarke, Laura, Halai, Reena, Kirton, Christopher M., Kolb-Kokocinski, Anja, Beales, Philip, Birney, Ewan, Danovi, Davide, Lamond, Angus I., Ouwehand, Willem H., Vallier, Ludovic, Watt, Fiona M., Durbin, Richard, Stegle, Oliver, and Gaffney, Daniel J.
- Subjects
Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Author(s): Helena Kilpinen; Angela Goncalves; Andreas Leha; Vackar Afzal; Kaur Alasoo; Sofie Ashford; Sendu Bala; Dalila Bensaddek; Francesco Paolo Casale; Oliver J. Culley; Petr Danecek; Adam Faulconbridge; Peter W. Harrison; [...]
- Published
- 2017
- Full Text
- View/download PDF
6. Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors
- Author
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Vigilante, Alessandra, Laddach, Anna, Moens, Nathalie, Meleckyte, Ruta, Leha, Andreas, Ghahramani, Arsham, Culley, Oliver J, Kathuria, Annie, Hurling, Chloe, Vickers, Alice, Wiseman, Erika, Tewary, Mukul, Zandstra, Peter W, HipSci Consortium, Durbin, Richard, Fraternali, Franca, Stegle, Oliver, Birney, Ewan, Luscombe, Nicholas M, Danovi, Davide, Watt, Fiona M, Durbin, Richard [0000-0002-9130-1006], and Apollo - University of Cambridge Repository
- Subjects
iPSC ,Induced Pluripotent Stem Cells ,Gene Expression ,cell adhesion ,Cell Differentiation ,Tumour Biology ,Polymorphism, Single Nucleotide ,Cell Line ,Mice ,Phenotype ,Biological Variation, Population ,fibronectin ,stem cells ,SNV ,genetic variation ,high content imaging ,Animals ,Humans ,stem cell niche ,Transcriptome ,Genetics & Genomics ,Computational & Systems Biology ,dimensionality reduction ,Cell Proliferation - Abstract
Large cohorts of human induced pluripotent stem cells (iPSCs) from healthy donors are a potentially powerful tool for investigating the relationship between genetic variants and cellular behavior. Here, we integrate high content imaging of cell shape, proliferation, and other phenotypes with gene expression and DNA sequence datasets from over 100 human iPSC lines. By applying a dimensionality reduction approach, Probabilistic Estimation of Expression Residuals (PEER), we extracted factors that captured the effects of intrinsic (genetic concordance between different cell lines from the same donor) and extrinsic (cell responses to different fibronectin concentrations) conditions. We identify genes that correlate in expression with intrinsic and extrinsic PEER factors and associate outlier cell behavior with genes containing rare deleterious non-synonymous SNVs. Our study, thus, establishes a strategy for examining the genetic basis of inter-individual variability in cell behavior.
- Published
- 2019
- Full Text
- View/download PDF
7. Identifying Extrinsic versus Intrinsic Drivers of Variation in Cell Behavior in Human iPSC Lines from Healthy Donors
- Author
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Vigilante, Alessandra, primary, Laddach, Anna, additional, Moens, Nathalie, additional, Meleckyte, Ruta, additional, Leha, Andreas, additional, Ghahramani, Arsham, additional, Culley, Oliver J., additional, Kathuria, Annie, additional, Hurling, Chloe, additional, Vickers, Alice, additional, Wiseman, Erika, additional, Tewary, Mukul, additional, Zandstra, Peter W., additional, Durbin, Richard, additional, Fraternali, Franca, additional, Stegle, Oliver, additional, Birney, Ewan, additional, Luscombe, Nicholas M., additional, Danovi, Davide, additional, and Watt, Fiona M., additional
- Published
- 2019
- Full Text
- View/download PDF
8. A high-content platform to characterise human induced pluripotent stem cell lines
- Author
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Leha, Andreas, Moens, Nathalie, Meleckyte, Ruta, Culley, Oliver J., Gervasio, Mia K., Kerz, Maximilian, Reimer, Andreas, Cain, Stuart A., Streeter, Ian, Folarin, Amos, Stegle, Oliver, Kielty, Cay M., Durbin, Richard, Watt, Fiona M., and Danovi, Davide
- Subjects
Biochemistry, Genetics and Molecular Biology(all) ,Molecular Biology - Abstract
Induced pluripotent stem cells (iPSCs) provide invaluable opportunities for future cell therapies as well as for studying human development, modelling diseases and discovering therapeutics. In order to realise the potential of iPSCs, it is crucial to comprehensively characterise cells generated from large cohorts of healthy and diseased individuals. The human iPSC initiative (HipSci) is assessing a large panel of cell lines to define cell phenotypes, dissect inter- and intra-line and donor variability and identify its key determinant components. Here we report the establishment of a high-content platform for phenotypic analysis of human iPSC lines. In the described assay, cells are dissociated and seeded as single cells onto 96-well plates coated with fibronectin at three different concentrations. This method allows assessment of cell number, proliferation, morphology and intercellular adhesion. Altogether, our strategy delivers robust quantification of phenotypic diversity within complex cell populations facilitating future identification of the genetic, biological and technical determinants of variance. Approaches such as the one described can be used to benchmark iPSCs from multiple donors and create novel platforms that can readily be tailored for disease modelling and drug discovery.
- Published
- 2016
9. Erratum: Corrigendum: Common genetic variation drives molecular heterogeneity in human iPSCs
- Author
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Kilpinen, Helena, primary, Goncalves, Angela, additional, Leha, Andreas, additional, Afzal, Vackar, additional, Alasoo, Kaur, additional, Ashford, Sofie, additional, Bala, Sendu, additional, Bensaddek, Dalila, additional, Casale, Francesco Paolo, additional, Culley, Oliver J., additional, Danecek, Petr, additional, Faulconbridge, Adam, additional, Harrison, Peter W., additional, Kathuria, Annie, additional, McCarthy, Davis, additional, McCarthy, Shane A., additional, Meleckyte, Ruta, additional, Memari, Yasin, additional, Moens, Nathalie, additional, Soares, Filipa, additional, Mann, Alice, additional, Streeter, Ian, additional, Agu, Chukwuma A., additional, Alderton, Alex, additional, Nelson, Rachel, additional, Harper, Sarah, additional, Patel, Minal, additional, White, Alistair, additional, Patel, Sharad R., additional, Clarke, Laura, additional, Halai, Reena, additional, Kirton, Christopher M., additional, Kolb-Kokocinski, Anja, additional, Beales, Philip, additional, Birney, Ewan, additional, Danovi, Davide, additional, Lamond, Angus I., additional, Ouwehand, Willem H., additional, Vallier, Ludovic, additional, Watt, Fiona M., additional, Durbin, Richard, additional, Stegle, Oliver, additional, and Gaffney, Daniel J., additional
- Published
- 2017
- Full Text
- View/download PDF
10. A high-content platform to characterise human induced pluripotent stem cell lines
- Author
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Leha, Andreas, primary, Moens, Nathalie, additional, Meleckyte, Ruta, additional, Culley, Oliver J., additional, Gervasio, Mia K., additional, Kerz, Maximilian, additional, Reimer, Andreas, additional, Cain, Stuart A., additional, Streeter, Ian, additional, Folarin, Amos, additional, Stegle, Oliver, additional, Kielty, Cay M., additional, Durbin, Richard, additional, Watt, Fiona M., additional, and Danovi, Davide, additional
- Published
- 2016
- Full Text
- View/download PDF
11. Erratum to : Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility
- Author
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Sevlever, Daniel, Zou, Fanggeng, Ma, Li, Carrasquillo, Sebastian, Crump, Michael G., Culley, Oliver J., Hunter, Talisha A., Bisceglio, Gina D., Younkin, Linda, Allen, Mariet, Carrasquillo, Minerva M., Sando, Sigrid B., Aasly, Jan O., Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Deák, Ferenc, Belbin, Olivia, Universitat Autònoma de Barcelona, Sevlever, Daniel, Zou, Fanggeng, Ma, Li, Carrasquillo, Sebastian, Crump, Michael G., Culley, Oliver J., Hunter, Talisha A., Bisceglio, Gina D., Younkin, Linda, Allen, Mariet, Carrasquillo, Minerva M., Sando, Sigrid B., Aasly, Jan O., Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Deák, Ferenc, Belbin, Olivia, and Universitat Autònoma de Barcelona
- Published
- 2015
12. Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer's Disease Pathology
- Author
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Zou, Fanggeng, Belbin, Olivia, Petersen, Ronald C, disease, Genetic and Environmental Risk for Alzheimer’s, Morgan, Kevin, Younkin, Steven G, Harold, Denise, Sims, Rebecca, Gerrish, Amy, Chapman, Jade, Moskvina, Valentina, Abraham, Richard, Carrasquillo, Minerva M, Hollingworth, Paul, Hamshere, Marian, Pahwa, Jaspreet Singh, Dowzell, Kimberley, Williams, Amy, Jones, Nicola, Thomas, Charlene, Stretton, Alexandra, Morgan, Angharad, Williams, Kate, Culley, Oliver J, Lovestone, Simon, Powell, John, Proitsi, Petroula, Lupton, Michelle K, Brayne, Carol, Rubinsztein, David C, Gill, Michael, Lawlor, Brian, Lynch, Aoibhinn, Hunter, Talisha A, Brown, Kristelle, Passmore, Peter, Craig, David, McGuinness, Bernadette, Johnston, Janet A, Todd, Stephen, Holmes, Clive, Mann, David, Smith, A David, Love, Seth, Ma, Li, Kehoe, Patrick G, Hardy, John, Guerreiro, Rita, Singleton, Andrew, Mead, Simon, Fox, Nick, Rossor, Martin, Collinge, John, Maier, Wolfgang, Jessen, Frank, Bisceglio, Gina D, Heun, Reiner, Schürmann, Britta, Ramirez, Alfredo, Herold, Christine, Lacour, André, Drichel, Dmitriy, van den Bussche, Hendrik, Heuser, Isabella, Kornhuber, Johannes, Wiltfang, Jens, Allen, Mariet, Dichgans, Martin, Frölich, Lutz, Hampel, Harald, Hüll, Michael, Rujescu, Dan, Goate, Alison, Kauwe, John S K, Cruchaga, Carlos, Nowotny, Petra, Morris, John C, Dickson, Dennis W, Mayo, Kevin, Livingston, Gill, Bass, Nicholas J, Gurling, Hugh, McQuillin, Andrew, Gwilliam, Rhian, Deloukas, Panagiotis, Nöthen, Markus M, Holmans, Peter, O'Donovan, Michael, Graff-Radford, Neill R, Owen, Michael J, Williams, Julie, and Wiltfang, Jens (Beitragende*r)
- Subjects
Male ,Pathology ,Heredity ,Medizin ,lcsh:Medicine ,Gene Expression ,genetics [Alzheimer Disease] ,pathology [Alzheimer Disease] ,0302 clinical medicine ,Polymorphism (computer science) ,Risk Factors ,genetics [Adaptor Proteins, Signal Transducing] ,Senile plaques ,lcsh:Science ,0303 health sciences ,Multidisciplinary ,Temporal Lobe ,Neurology ,genetics [Polymorphism, Single Nucleotide] ,Medicine ,Female ,Alzheimer's disease ,Research Article ,medicine.medical_specialty ,Genotypes ,genetics [Genetic Loci] ,Biology ,metabolism [RNA, Messenger] ,Polymorphism, Single Nucleotide ,metabolism [Temporal Lobe] ,Cell Line ,Molecular Genetics ,03 medical and health sciences ,metabolism [Adaptor Proteins, Signal Transducing] ,genetics [RNA, Messenger] ,Genetic Heterogeneity ,Apolipoproteins E ,Meta-Analysis as Topic ,Alzheimer Disease ,genetics [Haplotypes] ,medicine ,GAB2 protein, human ,Genetics ,Humans ,Genetic Predisposition to Disease ,ddc:610 ,RNA, Messenger ,Allele ,Genetic Association Studies ,030304 developmental biology ,Adaptor Proteins, Signal Transducing ,Aged ,Evolutionary Biology ,Population Biology ,Genetic heterogeneity ,lcsh:R ,Case-control study ,Computational Biology ,Neurofibrillary tangle ,pathology [Temporal Lobe] ,Human Genetics ,Epistasis, Genetic ,Odds ratio ,medicine.disease ,R1 ,Haplotypes ,Genetic Loci ,Case-Control Studies ,Postmortem Changes ,Genetics of Disease ,North America ,Genetic Polymorphism ,Epistasis ,genetics [Apolipoproteins E] ,lcsh:Q ,Dementia ,030217 neurology & neurosurgery ,Population Genetics - Abstract
GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p
- Published
- 2013
13. Human pluripotent stem cells on artificial microenvironments: a high content perspective
- Author
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Viswanathan, Priyalakshmi, primary, Gaskell, Terri, additional, Moens, Nathalie, additional, Culley, Oliver J., additional, Hansen, Darrick, additional, Gervasio, Mia K. R., additional, Yeap, Yee J., additional, and Danovi, Davide, additional
- Published
- 2014
- Full Text
- View/download PDF
14. Investigation of 15 of the top candidate genes for late-onset Alzheimer’s disease
- Author
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Belbin, Olivia, primary, Carrasquillo, Minerva M., additional, Crump, Michael, additional, Culley, Oliver J., additional, Hunter, Talisha A., additional, Ma, Li, additional, Bisceglio, Gina, additional, Zou, Fanggeng, additional, Allen, Mariet, additional, Dickson, Dennis W., additional, Graff-Radford, Neill R., additional, Petersen, Ronald C., additional, Morgan, Kevin, additional, and Younkin, Steven G., additional
- Published
- 2010
- Full Text
- View/download PDF
15. Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility.
- Author
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Sevlever, Daniel, Fanggeng Zou, Li Ma, Carrasquillo, Sebastian, Crump, Michael G., Culley, Oliver J., Hunter, Talisha A., Bisceglio, Gina D., Younkin, Linda, Allen, Mariet, Carrasquillo, Minerva M., Sando, Sigrid B., Aasly, Jan O., Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Morgan, Kevin, and Belbin, Olivia
- Subjects
GENETICS of Alzheimer's disease ,MEMBRANE proteins ,VESICLES (Cytology) ,PATHOLOGICAL physiology ,DISEASE susceptibility ,PROTEIN expression - Abstract
Background: Alzheimer's disease is a neurodegenerative disorder in which extracellular deposition of ß-amyloid (Aß) oligomers causes synaptic injury resulting in early memory loss, altered homeostasis, accumulation of hyperphosphorylated tau and cell death. Since proteins in the SNAP (Soluble N-ethylmaleimide-sensitive factor Attachment Protein) REceptors (SNARE) complex are essential for neuronal Aß release at pre-synaptic terminals, we hypothesized that genetically controlled SNARE expression could alter neuronal Aß release at the synapse and hence play an early role in Alzheimer's pathophysiology. Results: Here we report 5 polymorphisms in Vesicle-Associated Membrane Protein 1 (VAMP1), a gene encoding a member of the SNARE complex, associated with bidirectionally altered cerebellar VAMP1 transcript levels (all p < 0.05). At the functional level, we demonstrated that control of VAMP1 expression by heterogeneous knockdown in mice resulted in up to 74% reduction in neuronal Aß exocytosis (p < 0.001). We performed a case-control association study of the 5 VAMP1 expression regulating polymorphisms in 4,667 Alzheimer's disease patients and 6,175 controls to determine their contribution to Alzheimer's disease risk. We found that polymorphisms associated with increased brain VAMP1 transcript levels conferred higher risk for Alzheimer's disease than those associated with lower VAMP1 transcript levels (p = 0.03). Moreover, we also report a modest protective association for a common VAMP1 polymorphism with Alzheimer's disease risk (OR = 0.88, p = 0.03). This polymorphism was associated with decreased VAMP1 transcript levels (p = 0.02) and was functionally active in a dual luciferase reporter gene assay (p < 0.01). Conclusions: Genetically regulated VAMP1 expression in the brain may modify both Alzheimer's disease risk and may contribute to Alzheimer's pathophysiology. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
16. Linking Protective GAB2 Variants, Increased Cortical GAB2 Expression and Decreased Alzheimer’s Disease Pathology
- Author
-
Zou, Fanggeng, Belbin, Olivia, Carrasquillo, Minerva M., Culley, Oliver J., Hunter, Talisha A., Ma, Li, Bisceglio, Gina D., Allen, Mariet, Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Morgan, Kevin, and Younkin, Steven G.
- Subjects
SIGNAL recognition particle receptor ,GENE expression ,ALZHEIMER'S disease ,CARRIER proteins ,HETEROGENEITY ,META-analysis - Abstract
GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer’s disease (LOAD) with reported odds ratios (ORs) ranging from 0.75–0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61–1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61–0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82–0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10
−7 −9.3×10−6 ). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = −0.34, p = 0.0006) and senile plaque counts (r = −0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = −0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level. [ABSTRACT FROM AUTHOR]- Published
- 2013
- Full Text
- View/download PDF
17. Common genetic variation drives molecular heterogeneity in human iPSCs
- Author
-
Kilpinen, Helena, Goncalves, Angela, Leha, Andreas, Afzal, Vackar, Alasoo, Kaur, Ashford, Sofie, Bala, Sendu, Bensaddek, Dalila, Casale, Francesco Paolo, Culley, Oliver J, Danecek, Petr, Faulconbridge, Adam, Harrison, Peter W, Kathuria, Annie, McCarthy, Davis, McCarthy, Shane A, Meleckyte, Ruta, Memari, Yasin, Moens, Nathalie, Soares, Filipa, Mann, Alice, Streeter, Ian, Agu, Chukwuma A, Alderton, Alex, Nelson, Rachel, Harper, Sarah, Patel, Minal, White, Alistair, Patel, Sharad R, Clarke, Laura, Halai, Reena, Kirton, Christopher M, Kolb-Kokocinski, Anja, Beales, Philip, Birney, Ewan, Danovi, Davide, Lamond, Angus I, Ouwehand, Willem H, Vallier, Ludovic, Watt, Fiona M, Durbin, Richard, Stegle, Oliver, and Gaffney, Daniel J
- Subjects
Quality Control ,DNA Copy Number Variations ,Genotype ,Induced Pluripotent Stem Cells ,Quantitative Trait Loci ,Genetic Variation ,Cellular Reprogramming ,3. Good health ,Phenotype ,Gene Expression Regulation ,Organ Specificity ,Humans ,Transcriptome ,Cells, Cultured - Abstract
Technology utilizing human induced pluripotent stem cells (iPS cells) has enormous potential to provide improved cellular models of human disease. However, variable genetic and phenotypic characterization of many existing iPS cell lines limits their potential use for research and therapy. Here we describe the systematic generation, genotyping and phenotyping of 711 iPS cell lines derived from 301 healthy individuals by the Human Induced Pluripotent Stem Cells Initiative. Our study outlines the major sources of genetic and phenotypic variation in iPS cells and establishes their suitability as models of complex human traits and cancer. Through genome-wide profiling we find that 5-46% of the variation in different iPS cell phenotypes, including differentiation capacity and cellular morphology, arises from differences between individuals. Additionally, we assess the phenotypic consequences of genomic copy-number alterations that are repeatedly observed in iPS cells. In addition, we present a comprehensive map of common regulatory variants affecting the transcriptome of human pluripotent cells.
18. Erratum to: Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer’s pathophysiology and susceptibility
- Author
-
Sevlever, Daniel, Zou, Fanggeng, Ma, Li, Carrasquillo, Sebastian, Crump, Michael G., Culley, Oliver J., Hunter, Talisha A., Bisceglio, Gina D., Younkin, Linda, Allen, Mariet, Carrasquillo, Minerva M., Sando, Sigrid B., Aasly, Jan O., Dickson, Dennis W., Graff-Radford, Neill R., Petersen, Ronald C., Deák, Ferenc, and Belbin, Olivia
- Subjects
Cellular and Molecular Neuroscience ,Clinical Neurology ,Molecular Biology - Full Text
- View/download PDF
19. Erratum to: Genetically-controlled Vesicle-Associated Membrane Protein 1 expression may contribute to Alzheimer's pathophysiology and susceptibility.
- Author
-
Sevlever D, Zou F, Ma L, Carrasquillo S, Crump MG, Culley OJ, Hunter TA, Bisceglio GD, Younkin L, Allen M, Carrasquillo MM, Sando SB, Aasly JO, Dickson DW, Graff-Radford NR, Petersen RC, Deák F, and Belbin O
- Abstract
Following publication of this work, we noticed that we inadvertently failed to include Dr Ferenc Deák in the author list. The author list has now been corrected and the amended authors' contributions section has been modified accordingly below.
- Published
- 2015
- Full Text
- View/download PDF
20. Linking protective GAB2 variants, increased cortical GAB2 expression and decreased Alzheimer's disease pathology.
- Author
-
Zou F, Belbin O, Carrasquillo MM, Culley OJ, Hunter TA, Ma L, Bisceglio GD, Allen M, Dickson DW, Graff-Radford NR, Petersen RC, Morgan K, and Younkin SG
- Subjects
- Adaptor Proteins, Signal Transducing metabolism, Aged, Apolipoproteins E genetics, Case-Control Studies, Cell Line, Epistasis, Genetic, Female, Genetic Association Studies, Genetic Heterogeneity, Genetic Loci genetics, Haplotypes genetics, Humans, Male, Meta-Analysis as Topic, North America, Postmortem Changes, RNA, Messenger genetics, RNA, Messenger metabolism, Risk Factors, Temporal Lobe pathology, Adaptor Proteins, Signal Transducing genetics, Alzheimer Disease genetics, Alzheimer Disease pathology, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide genetics, Temporal Lobe metabolism
- Abstract
GRB-associated binding protein 2 (GAB2) represents a compelling genome-wide association signal for late-onset Alzheimer's disease (LOAD) with reported odds ratios (ORs) ranging from 0.75-0.85. We tested eight GAB2 variants in four North American Caucasian case-control series (2,316 LOAD, 2,538 controls) for association with LOAD. Meta-analyses revealed ORs ranging from (0.61-1.20) with no significant association (all p>0.32). Four variants were hetergeneous across the populations (all p<0.02) due to a potentially inflated effect size (OR = 0.61-0.66) only observed in the smallest series (702 LOAD, 209 controls). Despite the lack of association in our series, the previously reported protective association for GAB2 remained after meta-analyses of our data with all available previously published series (11,952-22,253 samples; OR = 0.82-0.88; all p<0.04). Using a freely available database of lymphoblastoid cell lines we found that protective GAB2 variants were associated with increased GAB2 expression (p = 9.5×10(-7)-9.3×10(-6)). We next measured GAB2 mRNA levels in 249 brains and found that decreased neurofibrillary tangle (r = -0.34, p = 0.0006) and senile plaque counts (r = -0.32, p = 0.001) were both good predictors of increased GAB2 mRNA levels albeit that sex (r = -0.28, p = 0.005) may have been a contributing factor. In summary, we hypothesise that GAB2 variants that are protective against LOAD in some populations may act functionally to increase GAB2 mRNA levels (in lymphoblastoid cells) and that increased GAB2 mRNA levels are associated with significantly decreased LOAD pathology. These findings support the hypothesis that Gab2 may protect neurons against LOAD but due to significant population heterogeneity, it is still unclear whether this protection is detectable at the genetic level.
- Published
- 2013
- Full Text
- View/download PDF
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