Author: "Elia J" / Topic: biology - Searchworks@Jio Institute Digital Library Search Results

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1. The effects of formalin fixation and fluid storage on stable isotopes in rodent hair

Author: Rebecca C. Terry, Mark Novak, David 'Tex' Taylor, and Elia J deJesus
Subjects: Ecology, Rodent, biology, Stable isotope ratio, Chemistry, biology.animal, Genetics, Animal Science and Zoology, Molecular biology, Ecology, Evolution, Behavior and Systematics, Nature and Landscape Conservation
Abstract: Stable isotopes are increasingly being used to unlock the wealth of information contained in specimens preserved in museum collections. However, preservation methods that employ formalin may confound ecological interpretations. To quantify the effects of formalin fixation and subsequent fluid storage in ethanol on the isotopic signatures of small mammal hair, we analyzed δ 13C and δ 15N values from specimens of seven rodent species that were sampled repeatedly both before and after varying lengths of formalin fixation (1–11 days) and ethanol storage (1–6 years). We supplemented these data with a 2-week fixation experiment using deer mice (Peromyscus maniculatus) in which no ethanol storage was employed. As expected, preservation in formalin and ethanol had no discernable effect on δ 15N values. In contrast, specimen δ 13C values decreased in a saturating fashion during formalin fixation and over subsequent years of fluid storage in ethanol. On the basis of models that we fit to these time series, we estimate the long-term effect of fixation and storage on δ 13C values to be −0.92‰ after 4 years. This biologically relevant shift in δ 13C values should be accounted for when inferring the diets of species from fluid-stored museum collections and when comparing across specimens with different preservation histories.
Published: 2021

2. Adaptation of the master antioxidant response connects metabolism, lifespan and feather development pathways in birds

Author: Gianni M Castiglione, Elia J. Duh, Zhenhua Xu, and Lingli Zhou
Subjects: 0301 basic medicine, Behavioural ecology, General Physics and Astronomy, medicine.disease_cause, Antioxidants, 0302 clinical medicine, Animal physiology, lcsh:Science, Phylogeny, media_common, Glutathione Transferase, chemistry.chemical_classification, Mutation, Multidisciplinary, Kelch-Like ECH-Associated Protein 1, biology, Longevity, Genomics, Adaptation, Physiological, Biological Evolution, Cell biology, Up-Regulation, Protein Transport, Neoaves, Cell signalling, Protein Binding, Proteasome Endopeptidase Complex, NF-E2-Related Factor 2, media_common.quotation_subject, Science, General Biochemistry, Genetics and Molecular Biology, Article, Birds, 03 medical and health sciences, medicine, Animals, Humans, Psychological repression, Cell Nucleus, Reactive oxygen species, Ubiquitination, General Chemistry, Feathers, Fibroblasts, biology.organism_classification, KEAP1, Oxidative Stress, 030104 developmental biology, HEK293 Cells, chemistry, Molecular evolution, lcsh:Q, Basal Metabolism, Adaptation, 030217 neurology & neurosurgery, Oxidative stress
Abstract: Birds (Aves) display high metabolic rates and oxygen consumption relative to mammals, increasing reactive oxygen species (ROS) formation. Although excess ROS reduces lifespan by causing extensive cellular dysfunction and damage, birds are remarkably long-lived. We address this paradox by identifying the constitutive activation of the NRF2 master antioxidant response in Neoaves (~95% of bird species), providing an adaptive mechanism capable of counterbalancing high ROS levels. We demonstrate that a KEAP1 mutation in the Neoavian ancestor disrupted the repression of NRF2 by KEAP1, leading to constitutive NRF2 activity and decreased oxidative stress in wild Neoaves tissues and cells. Our evidence suggests this ancient mutation induced a compensatory program in NRF2-target genes with functions beyond redox regulation—including feather development—while enabling significant metabolic rate increases that avoid trade-offs with lifespan. The strategy of NRF2 activation sought by intense clinical investigation therefore appears to have also unlocked a massively successful evolutionary trajectory., Fast metabolisms tend to shorten lifespans by increasing oxidative damage. This study identifies a gene mutation that keeps a key antioxidant response active, possibly allowing Neoaves bird species to avoid the tradeoff between rapid metabolism and longevity that challenges most mammals, including humans.
Published: 2020

3. In vivo characterization of emerging SARS-CoV-2 variant infectivity and human antibody escape potential

Author: Evan M. Bloch, Yu Jui Kung, John H. Lin, Tzyy Choou Wu, Liangmei He, Ya Chea Tsai, Ssu-Hsueh Tseng, Chien Fu Hung, Brandon Lam, Elia J. Duh, Gianni M Castiglione, Aaron M. Milstone, Aaron A.R. Tobian, Richard B. S. Roden, and Emily R Egbert
Subjects: QH301-705.5, Virulence, Plasma protein binding, In Vitro Techniques, Antibodies, Viral, General Biochemistry, Genetics and Molecular Biology, Neutralization, Article, Cell Line, Mice, Immune system, In vivo, Cricetinae, Nasopharynx, Animals, Humans, N501Y, Biology (General), COVID-19 Serotherapy, Infectivity, pseudovirus, biology, SARS-CoV-2, Immunization, Passive, in vivo modeling, immune escape, Respiratory infection, Genetic Variation, COVID-19, Virology, Antibodies, Neutralizing, Recombinant Proteins, HEK293 Cells, Immune System, Mutation, Spike Glycoprotein, Coronavirus, biology.protein, Antibody, Protein Binding
Abstract: As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads, variants with enhanced virulence and transmissibility have emerged. Although in vitro systems allow rapid characterization, they do not fully recapitulate the dynamic interaction of virions and neutralizing antibodies in the airway. Here, we demonstrate that the N501Y variant permits respiratory infection in unmodified mice. We utilize N501Y to survey in vivo pseudovirus infection dynamics and susceptibility to reinfection with the L452R (Los Angeles), K417N + E484K (South Africa), and L452R + K417N + E484Q (India) variants. Human coronavirus disease 2019 (COVID-19)+ or vaccinated antibody isotypes, titers, variant receptor binding domain (RBD) binding, and neutralization potential are studied, revealing numerous significant correlations. Immune escape of the K417N + E484K variant is observed because infection can be appreciated in the nasopharynx, but not lungs, of mice transferred with low-antibody-tier plasma. Conversely, near-complete protection is observed in animals receiving high-antibody-tier plasma, a phenomenon that can only be appreciated in vivo., Graphical abstract, Lam et al. develop a model of SARS-CoV-2 infection in laboratory mice. This allows researchers to study the threat of emerging variants in a more physiological context than by using cell culture systems. Interactions between SARS-CoV-2 variants and immunity are explored in the airway of mice.
Published: 2021

4. The ancient cardioprotective mechanisms of ACE2 bestow SARS-CoV-2 with a wide host range

Author: Lingli Zhou, Chien Fu Hung, Gianni M Castiglione, Zhenhua Xu, Zachary Neiman, and Elia J. Duh
Subjects: Carboxypeptidase activity, Genetics, Rodent, Mechanism (biology), Range (biology), biology.animal, fungi, Epistasis, Biology, Permissive, Phenotype, Virus
Abstract: SARS-CoV-2 infects a broader range of mammalian species than previously anticipated, suggesting there may be additional unknown hosts wherein the virus can evolve and potentially circumvent effective vaccines. We find that SARS-CoV-2 gains a wide host range by binding ACE2 sites essential for ACE2 carboxypeptidase activity. Six mutations found only in rodent species immune to SARS-CoV-2 are sufficient to abolish viral binding to human and dog ACE2. This is achieved through context-dependent mutational effects (intramolecular epistasis) conserved despite ACE2 sequence divergence between species. Across mammals, this epistasis generates sequence-function diversity, but through structures all bound by SARS-CoV-2. Mutational trajectories to the mouse conformation not bound by SARS-CoV-2 are blocked, by single mutations functionally deleterious in isolation, but compensatory in combination, explaining why human polymorphisms at these sites are virtually non-existent. Closed to humans, this path was opened to rodents via permissive cardiovascular phenotypes and ancient increases to ACE2 activity, serendipitously granting SARS-CoV-2 immunity. This reveals how ancient evolutionary trajectories are linked with unprecedented phenotypes such as COVID-19 and suggests extreme caution should be taken to monitor and prevent emerging animal reservoirs of SARS-CoV-2.One sentence summaryA conserved mechanism essential for ACE2 catalytic activity is exploited by SARS-CoV-2 binding, allowing the virus to infect a wide range of species.
Published: 2021

5. Nrf2 protects photoreceptor cells from photo-oxidative stress induced by blue light

Author: Zhenhua Xu, Caiying Wu, Elia J. Duh, Wan Ju Chen, Hideaki Hara, and Yoshiki Kuse
Subjects: 0301 basic medicine, Programmed cell death, Light, NF-E2-Related Factor 2, Blotting, Western, Apoptosis, Cell Count, Endogeny, Oxidative phosphorylation, Biology, Real-Time Polymerase Chain Reaction, medicine.disease_cause, environment and public health, Neuroprotection, Article, Cell Line, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Botany, medicine, Animals, Photoreceptor Cells, chemistry.chemical_classification, Gene knockdown, Reactive oxygen species, Retinal Degeneration, Retinal, respiratory system, Sensory Systems, Cell biology, Oxidative Stress, Ophthalmology, 030104 developmental biology, Gene Expression Regulation, chemistry, RNA, sense organs, Reactive Oxygen Species, Oxidative stress
Abstract: Oxidative stress plays a key role in age-related macular degeneration and hereditary retinal degenerations. Light damage in rodents has been used extensively to model oxidative stress-induced photoreceptor degeneration, and photo-oxidative injury from blue light is particularly damaging to photoreceptors. The endogenous factors protecting photoreceptors from oxidative stress, including photo-oxidative stress, are continuing to be elucidated. In this study, we evaluated the effect of blue light exposure on photoreceptors and its relationship to Nrf2 using cultured murine photoreceptor (661W) cells. 661W cells were exposed to blue light at 2500 lux. Exposure to blue light for 6–24 h resulted in a significant increase in intracellular reactive oxygen species (ROS) and death of 661W cells in a time-dependent fashion. Blue light exposure resulted in activation of Nrf2, as indicated by an increase in nuclear translocation of Nrf2. This was associated with a significant induction of expression of Nrf2 as well as an array of Nrf2 target genes, including antioxidant genes, as indicated by quantitative reverse transcription PCR (qRT-PCR). In order to determine the functional role of Nrf2, siRNA-mediated knockdown studies were performed. Nrf2-knockdown in 661W cells resulted in significant exacerbation of blue light-induced reactive oxygen species levels as well as cell death. Taken together, these findings indicate that Nrf2 is an important endogenous protective factor against oxidative stress in photoreceptor cells. This suggests that drugs targeting Nrf2 could be considered as a neuroprotective strategy for photoreceptors in AMD and other retinal conditions.
Published: 2017

6. Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Author: Demontis, D, Walters, R, Martin, J, Mattheisen, M, Als, T, Agerbo, E, Baldursson, G, Belliveau, R, Bybjerg-Grauholm, J, Baekvad-Hansen, M, Cerrato, F, Chambert, K, Churchhouse, C, Dumont, A, Eriksson, N, Gandal, M, Goldstein, J, Grasby, K, Grove, J, Gudmundsson, O, Hansen, C, Hauberg, M, Hollegaard, M, Howrigan, D, Huang, H, Maller, J, Martin, A, Martin, N, Moran, J, Pallesen, J, Palmer, D, Pedersen, C, Pedersen, M, Poterba, T, Poulsen, J, Ripke, S, Robinson, E, Satterstrom, F, Stefansson, H, Stevens, C, Turley, P, Walters, G, Won, H, Wright, M, Andreassen, O, Asherson, P, Burton, C, Boomsma, D, Cormand, B, Dalsgaard, S, Franke, B, Gelernter, J, Geschwind, D, Hakonarson, H, Haavik, J, Kranzler, H, Kuntsi, J, Langley, K, Lesch, K, Middeldorp, C, Reif, A, Rohde, L, Roussos, P, Schachar, R, Sklar, P, Sonuga-Barke, E, Sullivan, P, Thapar, A, Tung, J, Waldman, I, Medland, S, Stefansson, K, Nordentoft, M, Hougaard, D, Werge, T, Mors, O, Mortensen, P, Daly, M, Faraone, S, Borglum, A, Neale, B, Albayrak, O, Anney, R, Arranz, M, Banaschewski, T, Bau, C, Biederman, J, Buitelaar, J, Casas, M, Charach, A, Crosbie, J, Dempfle, A, Doyle, A, Ebstein, R, Elia, J, Freitag, C, Focker, M, Gill, M, Grevet, E, Hawi, Z, Hebebrand, J, Herpertz-Dahlmann, B, Hervas, A, Hinney, A, Hohmann, S, Holmans, P, Hutz, M, Ickowitz, A, Johansson, S, Kent, L, Kittel-Schneider, S, Lambregts-Rommelse, N, Lehmkuhl, G, Loo, S, McGough, J, Meyer, J, Mick, E, Middletion, F, Miranda, A, Mota, N, Mulas, F, Mulligan, A, Nelson, F, Nguyen, T, Oades, R, O'Donovan, M, Owen, M, Palmason, H, Ramos-Quiroga, J, Renner, T, Ribases, M, Rietschel, M, Rivero, O, Romanos, J, Romanos, M, Rothenberger, A, Royers, H, Sanchez-Mora, C, Scherag, A, Schimmelmann, B, Schafer, H, Sergeant, J, Sinzig, J, Smalley, S, Steinhausen, H, Thompson, M, Todorov, A, Vasquez, A, Walitza, S, Wang, Y, Warnke, A, Williams, N, Witt, S, Yang, L, Zayats, T, Zhang-James, Y, Smith, G, Davies, G, Ehli, E, Evans, D, Fedko, I, Greven, C, Groen-Blokhuis, M, Guxens, M, Hammerschlag, A, Hartman, C, Heinrich, J, Hottenga, J, Hudziak, J, Jugessur, A, Kemp, J, Krapohl, E, Murcia, M, Myhre, R, Nolte, I, Nyholt, D, Ormel, J, Ouwens, K, Pappa, I, Pennell, C, Plomin, R, Ring, S, Standl, M, Stergiakouli, E, St Pourcain, B, Stoltenberg, C, Sunyer, J, Thiering, E, Tiemeier, H, Tiesler, C, Timpson, N, Trzaskowski, M, van der Most, P, Vilor-Tejedor, N, Wang, C, Whitehouse, A, Zhao, H, Agee, M, Alipanahi, B, Auton, A, Bell, R, Bryc, K, Elson, S, Fontanillas, P, Furlotte, N, Hinds, D, Hromatka, B, Huber, K, Kleinman, A, Litterman, N, McIntyre, M, Mountain, J, Northover, C, Pitts, S, Sathirapongsasuti, J, Sazonova, O, Shelton, J, Shringarpure, S, Tian, C, Vacic, V, Wilson, C, ADHD Working Grp Psychiat Genomics, Early Lifecourse Genetic, 23andMe Res Team, Institute for Molecular Medicine Finland, Centre of Excellence in Complex Disease Genetics, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, Psychiatry, ADHD Working Group of the Psychiatric Genomics Consortium (PGC), 23andme Research Team, University of St Andrews. Cellular Medicine Division, University of St Andrews. Institute of Behavioural and Neural Sciences, University of St Andrews. School of Medicine, Child and Adolescent Psychiatry / Psychology, Erasmus MC other, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Neuropsychology, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, APH - Personalized Medicine, Clinical Child and Family Studies, LEARN! - Child rearing, and APH - Methodology
Subjects: Netherlands Twin Register (NTR), Male, Trastorns per dèficit d'atenció amb hiperactivitat en els infants, LD SCORE REGRESSION, Medizin, Genome-wide association study, US CHILDREN, Genoma humà, Attention deficit disorder with hyperactivity in children, Medical and Health Sciences, Cohort Studies, 0302 clinical medicine, 2.1 Biological and endogenous factors, POLYGENIC RISK, Aetiology, Child, IDENTIFIES 11, SEXUAL-BEHAVIOR, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, Pediatric, 0303 health sciences, education.field_of_study, Genome, Genetic Predisposition to Disease/genetics, 1184 Genetics, developmental biology, physiology, Brain, 3rd-DAS, Single Nucleotide, Biological Sciences, Polymorphism, Single Nucleotide/genetics, 3. Good health, Mental Health, Meta-analysis, Child, Preschool, Genetic Loci/genetics, Genome-Wide Association Study/methods, Trastorns per dèficit d'atenció amb hiperactivitat en els adults, Attention Deficit Disorder (ADD), Female, Attention Deficit Disorder with Hyperactivity/genetics, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, SDG 4 - Quality Education, Clinical psychology, Risk, Adolescent, DEFICIT HYPERACTIVITY DISORDER, Concordance, Population, PROVIDES INSIGHTS, QH426 Genetics, Biology, Quantitative trait locus, Brain/physiology, Polymorphism, Single Nucleotide, 23andMe Research Team, behavioral disciplines and activities, Gene Expression Regulation/genetics, Article, 150 000 MR Techniques in Brain Function, GENETIC ARCHITECTURE, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Clinical Research, Behavioral and Social Science, mental disorders, medicine, Genetics, Attention deficit hyperactivity disorder, Humans, Genetic Predisposition to Disease, Polymorphism, education, Preschool, QH426, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], ASSOCIATION METAANALYSIS, Prevention, Human Genome, Case-control study, MAJOR DEPRESSION, medicine.disease, Attention Deficit Hyperactivity Disorder (ADHD), Genetic architecture, Brain Disorders, ADHD Working Group of the Psychiatric Genomics Consortium, Gene Expression Regulation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, RC0321, Attention deficit disorder with hyperactivity in adults, 3111 Biomedicine, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract: Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits. Postprint
Published: 2019

7. Nrf2 promotes reparative angiogenesis through regulation of NADPH oxidase-2 in oxygen-induced retinopathy

Author: Junsong Gong, Yanhong Wei, Elia J. Duh, and Zhenhua Xu
Subjects: Vascular Endothelial Growth Factor A, 0301 basic medicine, Angiogenesis, medicine.medical_treatment, medicine.disease_cause, environment and public health, Biochemistry, Mice, chemistry.chemical_compound, 0302 clinical medicine, Ischemia, Mice, Knockout, NADPH oxidase, Neovascularization, Pathologic, Receptors, Notch, biology, Intracellular Signaling Peptides and Proteins, respiratory system, 030220 oncology & carcinogenesis, NADPH Oxidase 2, medicine.symptom, Signal Transduction, NF-E2-Related Factor 2, Notch signaling pathway, Inflammation, Revascularization, digestive system, Retina, Article, 03 medical and health sciences, Physiology (medical), medicine, Animals, Adaptor Proteins, Signal Transducing, Calcium-Binding Proteins, Retinitis, Membrane Proteins, Retinal, medicine.disease, Mice, Inbred C57BL, Oxygen, Oxidative Stress, 030104 developmental biology, Animals, Newborn, Gene Expression Regulation, chemistry, Immunology, biology.protein, Cancer research, Oxidative stress
Abstract: Revascularization of ischemic tissue is a highly desirable outcome in multiple diseases, including cardiovascular diseases and ischemic retinopathies. Oxidative stress and inflammation are both known to play a role in suppressing reparative angiogenesis in ischemic disease models including oxygen-induced retinopathy (OIR), but the regulatory molecules governing these pathophysiologic processes in retinal ischemia are largely unknown. Nrf2 is a major stress-response transcription factor that has been implicated in regulating ischemic angiogenesis in the retina and other tissue beds. Using Nrf2-deficient mice, we investigated the effects of Nrf2 in regulating revascularization and modulating the retinal tissue milieu during ischemia. Strikingly, Nrf2’s beneficial effect on reparative angiogenesis only became manifested in the later phase of ischemia in OIR, from postnatal day 14 (P14) to P17. This was temporally associated with a reduction in both oxidative stress and inflammatory mediators in wild-type compared to Nrf2(−/−) mice. Nrf2(−/−) retinas exhibited an increase in VEGF but also induction of anti-angiogenic Dll4-Notch signaling. NADPH oxidase (NOX), and especially NOX2, is a major pathogenic molecule and a particularly important contributor to oxidative stress in multiple retinal disease processes. Nrf2(−/−) mice exhibited a significant exacerbation of NOX2 induction in OIR that manifested in the later phases of ischemia. Pharmacologic inhibition of NADPH oxidase abrogated the adverse effect of Nrf2 deficiency on reparative angiogenesis. Taken together, this suggests that Nrf2 is an important regulator of the retinal milieu during tissue ischemia, and that the Nrf2/NOX2 balance may play a critical role in determining the fate of ischemic revascularization.
Published: 2016

8. Seeking clarity on retinal findings in patients with COVID-19

Author: Elia J. Duh
Subjects: 2019-20 coronavirus outbreak, biology, Coronavirus disease 2019 (COVID-19), business.industry, Retinal, General Medicine, medicine.disease, biology.organism_classification, Virology, Pneumonia, chemistry.chemical_compound, chemistry, Correspondence, Pandemic, medicine, In patient, business, Coronavirus Infections, Betacoronavirus
Published: 2020

9. Pigment epithelium-derived factor inhibits retinal microvascular dysfunction induced by 12/15-lipoxygenase-derived eicosanoids

Author: Mohamed Al-Shabrawey, Ahmed Ibrahim, Sylvia B. Smith, Elia J. Duh, Nasser Rizk, Sally Elshafey, Amany Tawfik, Shanu Markand, and Khaled A. Hussein
Subjects: Angiogenesis, Retinal Neovascularization, Neovascularization, Mice, chemistry.chemical_compound, Diabetic retinopathy, Hydroxyeicosatetraenoic Acids, Arachidonate 15-Lipoxygenase, 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid, Cells, Cultured, Mice, Knockout, Membrane Glycoproteins, NADPH oxidase, biology, NF-kappa B, Hydroxyeicosatetraenoic acid, Retinal inflammation, Anatomy, Intercellular Adhesion Molecule-1, Vascular endothelial growth factor, Intravitreal Injections, NADPH Oxidase 2, PEDF, cardiovascular system, medicine.symptom, Signal Transduction, medicine.medical_specialty, Ependymoglial Cells, Vascular Cell Adhesion Molecule-1, Arachidonate 12-Lipoxygenase, Retina, Article, Retinal vascular leakage, Diabetes Mellitus, Experimental, 12/15 HETEs, Internal medicine, medicine, Animals, Humans, Nerve Growth Factors, Eye Proteins, Molecular Biology, Serpins, Diabetic Retinopathy, Interleukin-6, Tumor Necrosis Factor-alpha, Acetophenones, Endothelial Cells, NADPH Oxidases, Retinal, Cell Biology, 12/15-Lipoxygenase, Endocrinology, Gene Expression Regulation, chemistry, Apocynin, Zonula Occludens-1 Protein, biology.protein
Abstract: We recently demonstrated that 12/15-lipoxygenase (LOX) derived metabolites, hydroxyeicosatetraenoic acids (HETEs), contribute to diabetic retinopathy (DR) via NADPH oxidase (NOX) and disruption of the balance in retinal levels of the vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF). Here, we test whether PEDF ameliorates retinal vascular injury induced by HETEs and the underlying mechanisms. Furthermore, we pursue the causal relationship between LOX–NOX system and regulation of PEDF expression during DR. For these purposes, we used an experimental eye model in which normal mice were injected intravitreally with 12-HETE with/without PEDF. Thereafter, fluorescein angiography (FA) was used to evaluate the vascular leakage, followed by optical coherence tomography (OCT) to assess the presence of angiogenesis. FA and OCT reported an increased vascular leakage and pre-retinal neovascularization, respectively, in response to 12-HETE that were not observed in the PEDF-treated group. Moreover, PEDF significantly attenuated the increased levels of vascular cell and intercellular adhesion molecules, VCAM-1 and ICAM-1, elicited by 12-HETE injection. Accordingly, the direct relationship between HETEs and PEDF has been explored through in-vitro studies using Müller cells (rMCs) and human retinal endothelial cells (HRECs). The results showed that 12- and 15-HETEs triggered the secretion of TNF-α and IL-6, as well as activation of NFκB in rMCs and significantly increased permeability and reduced zonula occludens protein-1 (ZO-1) immunoreactivity in HRECs. All these effects were prevented in PEDF-treated cells. Furthermore, interest in PEDF regulation during DR has been expanded to include NOX system. Retinal PEDF was significantly restored in diabetic mice treated with NOX inhibitor, apocynin, or lacking NOX2 up to 80% of the control level. Collectively, our findings suggest that interfering with LOX–NOX signaling opens up a new direction for treating DR by restoring endogenous PEDF that carries out multilevel vascular protective functions. National Eye Institute 5R01EY023315-02, Qatar National Research Fund NPRP 4-1046-3-284, and Vision Discovery Institute (MA), Mr. and Mrs. Richards travel award (ASI).
Published: 2015

10. Transcription Factor MEF2C Suppresses Endothelial Cell Inflammation via Regulation of NF-κB and KLF2

Author: Zhenhua Xu, Lijuan Wu, Liudmila Cebotaru, Takeshi Yoshida, Debasish Maiti, and Elia J. Duh
Subjects: Endothelium, Physiology, Angiogenesis, Clinical Biochemistry, Cell Biology, Biology, Cell biology, Endothelial stem cell, Vascular endothelial growth factor B, Vascular endothelial growth factor A, medicine.anatomical_structure, Vascular endothelial growth factor C, KLF2, medicine, Tumor necrosis factor alpha
Abstract: Endothelial cells play a major role in the initiation and perpetuation of the inflammatory process in health and disease, including their pivotal role in leukocyte recruitment. The role of pro-inflammatory transcription factors in this process has been well-described, including NF-κB. However, much less is known regarding transcription factors that play an anti-inflammatory role in endothelial cells. Myocyte enhancer factor 2 C (MEF2C) is a transcription factor known to regulate angiogenesis in endothelial cells. Here, we report that MEF2C plays a critical function as an inhibitor of endothelial cell inflammation. Tumor necrosis factor (TNF)-α inhibited MEF2C expression in endothelial cells. Knockdown of MEF2C in endothelial cells resulted in the upregulation of pro-inflammatory molecules and stimulated leukocyte adhesion to endothelial cells. MEF2C knockdown also resulted in NF-κB activation in endothelial cells. Conversely, MEF2C overexpression by adenovirus significantly repressed TNF-α induction of pro-inflammatory molecules, activation of NF-κB, and leukocyte adhesion to endothelial cells. This inhibition of leukocyte adhesion by MEF2C was partially mediated by induction of KLF2. In mice, lipopolysaccharide (LPS)-induced leukocyte adhesion to the retinal vasculature was significantly increased by endothelial cell-specific ablation of MEF2C. Taken together, these results demonstrate that MEF2C is a novel negative regulator of inflammation in endothelial cells and may represent a therapeutic target for vascular inflammation.
Published: 2015

11. Deletion of Placental Growth Factor Prevents Diabetic Retinopathy and Is Associated With Akt Activation and HIF1α-VEGF Pathway Inhibition

Author: Hu Huang, Jianbo He, Da’Kuawn Johnson, Yanhong Wei, Ying Liu, Shuang Wang, Gerard A. Lutty, Elia J. Duh, Peter Carmeliet, and Richard D. Semba
Subjects: Placental growth factor, 0303 health sciences, medicine.medical_specialty, Complications, biology, Endocrinology, Diabetes and Metabolism, Growth factor, medicine.medical_treatment, Leukostasis, Diabetic retinopathy, medicine.disease, Nitric oxide synthase, 03 medical and health sciences, Vascular endothelial growth factor A, 0302 clinical medicine, medicine.anatomical_structure, Endocrinology, Internal medicine, 030221 ophthalmology & optometry, Internal Medicine, medicine, biology.protein, Pericyte, Protein kinase B, 030304 developmental biology
Abstract: A new diabetic mouse strain, the Akita.PlGF knockout (−/−), was generated to study the role of placental growth factor (PlGF) in the pathogenesis of diabetic retinopathy (DR). PlGF deletion did not affect blood glucose but reduced the body weight of Akita.PlGF−/− mice. Diabetes-induced retinal cell death, capillary degeneration, pericyte loss, and blood-retinal barrier breakdown were prevented in these mice. Protein expression of PlGF was upregulated by diabetes, particularly in vascular cells. Diabetes-induced degradation of ZO-1 and VE-cadherin was reversed due to PlGF deficiency; their expression was correlated with that of sonic hedgehog and angiopoietin-1. PlGF deletion in Akita mice resulted in an increased Akt phosphorylation. Diabetes-activated hypoxia-inducible factor (HIF)1α–vascular endothelial growth factor (VEGF) pathway, including expression of HIF1α, VEGF, VEGFR1–3, and the extent of phospho (p)-VEGFR1, p-VEGFR2, and p–endothelial nitric oxide synthase, was inhibited in the retinas of diabetic PlGF−/− mice. However, expression of intercellular adhesion molecule-1, vascular cell adhesion molecule-1, CD11b, and CD18 was not inhibited by PlGF deletion, nor was retinal leukostasis. These results suggest that PlGF is critical for the development of DR, and its genetic deletion protects the retina from diabetic damage. Protective mechanisms are associated with Akt activation and HIF1α-VEGF pathway inhibition, but independent of retinal leukostasis in the retinas of diabetic PlGF−/− mice.
Published: 2014

12. Gene delivery nanoparticles specific for human microvasculature and macrovasculature

Author: Jordan J. Green, Elia J. Duh, Ron B. Shmueli, Zhenhua Xu, and Joel C. Sunshine
Subjects: Polymers, Biomedical Engineering, Pharmaceutical Science, Medicine (miscellaneous), Bioengineering, Biology, Gene delivery, Transfection, Article, Umbilical vein, Cell Line, chemistry.chemical_compound, In vivo, Human Umbilical Vein Endothelial Cells, Humans, General Materials Science, fungi, Endothelial Cells, Retinal Vessels, Retinal, DNA, In vitro, Endothelial stem cell, chemistry, Cell culture, Microvessels, embryonic structures, Immunology, Cancer research, Nanoparticles, Molecular Medicine
Abstract: Endothelial cell dysfunction is a critical component of ocular diseases such as age-related macular degeneration and diabetic retinopathy. An important limitation in endothelial cell research is the difficulty in achieving efficient transfection of these cells. A new polymer library was here synthesized and utilized to find polymeric nanoparticles that can transfect macrovascular (human umbilical vein, HUVECs) and microvascular (human retinal, HRECs) endothelial cells. Nanoparticles were synthesized that can achieve transfection efficiency of up to 85% for HRECs and 65% for HUVECs. These nanoparticle systems enable high levels of expression while avoiding problems associated with viral gene delivery. The polymeric nanoparticles also show cell-specific behavior, with a high correlation between microvascular and macrovascular transfection (R 2 = 0.81) but low correlation between retinal endothelial and retinal epithelial transfection (R 2 = 0.21). These polymeric nanoparticles can be used in vitro as experimental tools and potentially in vivo to target and treat vascular-specific diseases. From the Clinical Editor Polymeric nanoparticles were synthesized with the goal of transfecting endothelial cells, which are commonly considered difficult targets. The authors report excellent transfection efficiency of up to 85% for human retinal and 65% for human umbilical vein endothelial cells. These NPs can be used in vitro as experimental tools and potentially in vivo to target and treat vascular-specific diseases.
Published: 2012

13. MEF2C Ablation in Endothelial Cells Reduces Retinal Vessel Loss and Suppresses Pathologic Retinal Neovascularization in Oxygen-Induced Retinopathy

Author: Debasish Maiti, Zhenhua Xu, Junsong Gong, Lijuan Wu, John J. Schwarz, Elia J. Duh, and Linh Vong
Subjects: medicine.medical_specialty, Endothelium, Angiogenesis, Apoptosis, Mice, Transgenic, Retinal Neovascularization, Biology, Pathology and Forensic Medicine, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Internal medicine, Blood-Retinal Barrier, medicine, Animals, Humans, Retinopathy of Prematurity, MEF2C, RNA, Small Interfering, Cells, Cultured, 030304 developmental biology, Mice, Knockout, Tube formation, 0303 health sciences, MEF2 Transcription Factors, Infant, Newborn, Endothelial Cells, Retinal Vessels, Regular Article, Retinal, Retinopathy of prematurity, medicine.disease, Oxygen, Endothelial stem cell, Oxidative Stress, medicine.anatomical_structure, Endocrinology, Myogenic Regulatory Factors, chemistry, Gene Knockdown Techniques, Cancer research, Endothelium, Vascular, 030217 neurology & neurosurgery, Retinopathy
Abstract: Ischemic retinopathies, including retinopathy of prematurity and diabetic retinopathy, are major causes of blindness. Both have two phases, vessel loss and consequent hypoxia-driven pathologic retinal neovascularization, yet relatively little is known about the transcription factors regulating these processes. Myocyte enhancer factor 2 (MEF2) C, a member of the MEF2 family of transcription factors that plays an important role in multiple developmental programs, including the cardiovascular system, seems to have a significant functional role in the vasculature. We, therefore, generated endothelial cell (EC)–specific MEF2C-deficient mice and explored the role of MEF2C in retinal vascularization during normal development and in a mouse model of oxygen-induced retinopathy. Ablation of MEF2C did not cause appreciable defects in normal retinal vascular development. However, MEF2C ablation in ECs suppressed vessel loss in oxygen-induced retinopathy and strongly promoted vascular regrowth, consequently reducing retinal avascularity. This finding was associated with suppression of pathologic retinal angiogenesis and blood-retinal barrier dysfunction. MEF2C knockdown in cultured retinal ECs using small-interfering RNAs rescued ECs from death and stimulated tube formation under stress conditions, confirming the endothelial-autonomous and antiangiogenic roles of MEF2C. HO-1 was induced by MEF2C knockdown in vitro and may play a role in the proangiogenic effect of MEF2C knockdown on retinal EC tube formation. Thus, MEF2C may play an antiangiogenic role in retinal ECs under stress conditions, and modulation of MEF2C may prevent pathologic retinal neovascularization.
Published: 2012

14. Inhibition of pathological retinal angiogenesis by the integrin αvβ3 antagonist tetraiodothyroacetic acid (tetrac)

Author: Elia J. Duh, Yanhong Wei, Zhenhua Xu, Junsong Gong, and Takeshi Yoshida
Subjects: Vascular Endothelial Growth Factor A, medicine.medical_specialty, Cell Survival, Angiogenesis, Blotting, Western, Integrin, Angiogenesis Inhibitors, Retinal Neovascularization, Article, Mice, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Cell Movement, Internal medicine, medicine, Animals, Humans, Phosphorylation, Erythropoietin, Cells, Cultured, Cell Proliferation, Mitogen-Activated Protein Kinase 1, Tube formation, Mitogen-Activated Protein Kinase 3, biology, Retinal, Retinopathy of prematurity, Integrin alphaVbeta3, medicine.disease, Sensory Systems, Mice, Inbred C57BL, Oxygen, Endothelial stem cell, Disease Models, Animal, Thyroxine, Ophthalmology, Endocrinology, chemistry, Intravitreal Injections, biology.protein, Cancer research, Endothelium, Vascular, medicine.drug, Retinopathy
Abstract: Retinal angiogenesis is a major cause of blindness in ischemic retinopathies including diabetic retinopathy and retinopathy of prematurity. Integrin αvβ3 is a promising therapeutic target for ocular angiogenesis, modulating the pro-angiogenic actions of multiple growth factors. In this study, we sought to determine the effects of the integrin αvβ3 antagonist tetra-iodothyroacetic acid (tetrac) on the angiogenic actions of VEGF and erythropoietin (EPO) in cultured human retinal endothelial cells. In addition, we investigated the effect of tetrac and a nanoparticulate formulation of tetrac on retinal angiogenesis in vivo, in the mouse oxygen-induced retinopathy (OIR) model. Tetrac inhibitory activity was evaluated in human retinal endothelial cells treated with VEGF and/or EPO. Endothelial cell proliferation, migration, and tube formation were assessed, in addition to phosphorylation of ERK1/2. For the studies of the oxygen-induced retinopathy model, C57BL/6 mice were exposed to 75% oxygen from postnatal day (P)7 to P12, and then returned to room air. Tetrac and tetrac-nanoparticle (tetrac-NP) were administered at P12 and P15 by either intraperitoneal or intravitreal injection. Retinal neovascularization was quantitated at P18. Tetrac significantly inhibited pro-angiogenic effects of VEGF and/or EPO on retinal endothelial cells, indicating that the angiogenic effects of both growth factors are dependent on integrin αvβ3. Retinal neovascularization in the OIR model was significantly inhibited by both tetrac and tetrac-NP. These results indicate that the integrin αvβ3 antagonist, tetrac, is an effective inhibitor of retinal angiogenesis. The ability of tetrac to inhibit the pro-angiogenic effect of both VEGF and EPO on retinal endothelial cells suggests that tetrac (and antagonism of integrin αvβ3) is a viable therapeutic strategy for proliferative diabetic retinopathy.
Published: 2012

15. Monomethyl fumarate promotes Nrf2-dependent neuroprotection in retinal ischemia-reperfusion

Author: Matthew J. Hartsock, Elia J. Duh, Hongkwan Cho, Zhenhua Xu, and Meihua He
Subjects: Retinal Ganglion Cells, Retinal degeneration, NF-E2-Related Factor 2, Immunology, Fumaric acid esters/monomethyl fumarate, Pharmacology, Biology, Neuroprotection, Retina, Mice, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Fumarates, Electroretinography, medicine, Animals, Neurodegeneration, Ganglion cell layer, Mice, Knockout, medicine.diagnostic_test, Dimethyl fumarate, Reverse Transcriptase Polymerase Chain Reaction, Research, Ischemia-reperfusion, General Neuroscience, Retinal Degeneration, Retinal, medicine.disease, Immunohistochemistry, 3. Good health, Mice, Inbred C57BL, Disease Models, Animal, Neuroprotective Agents, medicine.anatomical_structure, Gene Expression Regulation, Neurology, Biochemistry, chemistry, Reperfusion Injury, Reperfusion injury
Abstract: Background Retinal ischemia results in neuronal degeneration and contributes to the pathogenesis of multiple blinding diseases. Recently, the fumaric acid ester dimethyl fumarate (DMF) has been FDA-approved for the treatment of multiple sclerosis, based on its neuroprotective and anti-inflammatory effects. Its potential role as a neuroprotective agent for retinal diseases has received little attention. In addition, DMF’s mode of action remains elusive, although studies have suggested nuclear factor erythroid 2-related factor 2 (Nrf2) activation as an important mechanism. Here we investigated the neuroprotective role of monomethyl fumarate (MMF), the biologically active metabolite of DMF, in retinal ischemia-reperfusion (I/R) injury, and examined the role of Nrf2 in mediating MMF action. Methods Wild-type C57BL/6J and Nrf2 knockout (KO) mice were subjected to 90 min of retinal ischemia followed by reperfusion. Mice received daily intraperitoneal injection of MMF. Inflammatory gene expression was measured using quantitative reverse transcription PCR (qRT-PCR) at 48 h after I/R injury. Seven days after I/R, qRT-PCR for Nrf2 target gene expression, immunostaining for Müller cell gliosis and cell loss in the ganglion cell layer (GCL), and electroretinography for retinal function were performed. Results The results of this study confirmed that MMF reduces retinal neurodegeneration in an Nrf2-dependent manner. MMF treatment significantly increased the expression of Nrf2-regulated antioxidative genes, suppressed inflammatory gene expression, reduced Müller cell gliosis, decreased neuronal cell loss in the GCL, and improved retinal function measured by electroretinogram (ERG) after retinal I/R injury in wild-type mice. Importantly, these MMF-mediated beneficial effects were not observed in Nrf2 KO mice. Conclusions These results indicate that fumaric acid esters (FAEs) exert a neuronal protective function in the retinal I/R model and further validate Nrf2 modulation as a major mode of action of FAEs. This suggests that DMF and FAEs could be a potential therapeutic agent for activation of the Nrf2 pathway in retinal and possibly systemic diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12974-015-0452-z) contains supplementary material, which is available to authorized users.
Published: 2015

16. Nrf2 has a protective role against neuronal and capillary degeneration in retinal ischemia–reperfusion injury

Author: Takeshi Yoshida, Charles G. Eberhart, Junsong Gong, Ponvijay Kombairaju, Yanhong Wei, Zhenhua Xu, Michael B. Sporn, James T. Handa, and Elia J. Duh
Subjects: Pathology, medicine.medical_specialty, NF-E2-Related Factor 2, Gene Expression, Inflammation, Biology, digestive system, environment and public health, Biochemistry, Article, Antioxidants, Proinflammatory cytokine, Mice, chemistry.chemical_compound, Physiology (medical), medicine, Animals, Oleanolic Acid, Ganglion cell layer, Mice, Knockout, chemistry.chemical_classification, Retina, Reactive oxygen species, Neovascularization, Pathologic, Superoxide, Retinal Vessels, Retinal, Anatomy, respiratory system, medicine.disease, Capillaries, Mice, Inbred C57BL, medicine.anatomical_structure, chemistry, Cytoprotection, Reperfusion Injury, Nerve Degeneration, medicine.symptom, Reactive Oxygen Species, Reperfusion injury
Abstract: Retinal ischemia-reperfusion (I/R) involves an extensive increase in reactive oxygen species as well as proinflammatory changes that result in significant histopathologic damage, including neuronal and vascular degeneration. Nrf2 has a well-known cytoprotective role in many tissues, but its protective function in the retina is unclear. We investigated the possible role of Nrf2 as a protective mechanism in retinal ischemia-reperfusion injury using Nrf2(-/-) mice. I/R resulted in an increase in retinal levels of superoxide and proinflammatory mediators, as well as leukocyte infiltration of the retina and vitreous, in Nrf2(+/+) mice. These effects were greatly accentuated in Nrf2(-/-) mice. With regard to histopathologic damage, Nrf2(-/-) mice exhibited loss of cells in the ganglion cell layer and markedly accentuated retinal capillary degeneration, as compared to wild-type. Treatment with the Nrf2 activator CDDO-Me increased antioxidant gene expression and normalized I/R-induced superoxide in the retina in wild-type but not Nrf2(-/-) mice. CDDO-Me treatment abrogated retinal capillary degeneration induced by I/R in wild-type but not Nrf2(-/-) mice. These studies indicate that Nrf2 is an important cytoprotective mechanism in the retina in response to ischemia-reperfusion injury and suggest that pharmacologic induction of Nrf2 could be a new therapeutic strategy for retinal ischemia-reperfusion and other retinal diseases.
Published: 2011

17. Synthesis of 4-haloserotonin derivatives and synthesis of the toad alkaloid dehydrobufotenine

Author: Derrick L. J. Clive and Elia J. L. Stoffman
Subjects: biology, Chemistry, Stereochemistry, biology.animal, Alkaloid, Organic Chemistry, Drug Discovery, Organic chemistry, Toad, Dehydrobufotenine, Biochemistry, Conjugate
Abstract: 4-Chloro-, 4-bromo- and 4-iodoserotonin derivatives were synthesized from 4-halo-5-oxyindoles, themselves derived from coumarins. Synthesis of the 4-iodoserotonins involved conjugate addition of an allyl group to a 5-iodocoumarin, followed by conversion of the allyl group into an aminoethyl unit. One of the iodoserotonin derivatives was converted into the toad alkaloid dehydrobufotenine, which was isolated as its hydroiodide.
Published: 2010

18. Pigment Epithelium-Derived Factor Contributes to Insulin Resistance in Obesity

Author: Kyle L. Hoehn, Sarah M. Turpin, Maria Matzaris, Seamus Crowe, Matthew J. Watt, Elia J. Duh, Catherine Economou, David E. James, Andrea L. Hevener, and Lindsay E. Wu
Subjects: medicine.medical_specialty, Physiology, Lipolysis, medicine.medical_treatment, Mice, Obese, Adipose tissue, Protein Serine-Threonine Kinases, Biology, Mice, chemistry.chemical_compound, PEDF, Insulin resistance, Adipocyte, Internal medicine, medicine, Animals, Humans, Insulin, Nerve Growth Factors, Obesity, Extracellular Signal-Regulated MAP Kinases, Eye Proteins, Molecular Biology, Serpins, JNK Mitogen-Activated Protein Kinases, Cell Biology, Glucose clamp technique, medicine.disease, Mice, Inbred C57BL, Insulin receptor, Endocrinology, chemistry, Glucose Clamp Technique, biology.protein, Insulin Resistance, Metabolic syndrome, Signal Transduction
Abstract: SummaryObesity is a major risk factor for insulin resistance; however, the factors linking these disorders are not well defined. Herein, we show that the noninhibitory serine protease inhibitor, pigment epithelium-derived factor (PEDF), plays a causal role in insulin resistance. Adipocyte PEDF expression and serum levels are elevated in several rodent models of obesity and reduced upon weight loss and insulin sensitization. Lean mice injected with recombinant PEDF exhibited reduced insulin sensitivity during hyperinsulinemic-euglycemic clamps. Acute PEDF administration activated the proinflammatory serine/threonine kinases c-Jun terminal kinase and extracellular regulated kinase in both muscle and liver, which corresponded with reduced insulin signal transduction. Prolonged PEDF administration stimulated adipose tissue lipolysis, resulted in ectopic lipid deposition, and reduced insulin sensitivity, while neutralizing PEDF in obese mice enhanced insulin sensitivity. Overall, these results identify a causal role for PEDF in obesity-induced insulin resistance.
Published: 2009

19. Nrf2 in ischemic neurons promotes retinal vascular regeneration through regulation of semaphorin 6A

Author: Zhenhua Xu, Junsong Gong, Yanhong Wei, Rajesh K. Thimmulappa, Shyam Biswal, Derek S. Welsbie, Katherine L. Mitchell, and Elia J. Duh
Subjects: Angiogenesis, NF-E2-Related Factor 2, medicine.medical_treatment, Ischemia, Notch signaling pathway, Semaphorins, Biology, Revascularization, Retinal ganglion, Mice, Semaphorin, Conditional gene knockout, medicine, Animals, Regeneration, Neurons, Retina, Multidisciplinary, Neovascularization, Pathologic, Receptors, Notch, Retinal Vessels, Anatomy, medicine.disease, Cell biology, medicine.anatomical_structure, PNAS Plus, Endothelium, Vascular, Signal Transduction
Abstract: Delayed revascularization of ischemic neural tissue is a major impediment to preservation of function in central nervous system (CNS) diseases including stroke and ischemic retinopathies. Therapeutic strategies allowing rapid revascularization are greatly needed to reduce ischemia-induced cellular damage and suppress harmful pathologic neovascularization. However, key mechanisms governing vascular recovery in ischemic CNS, including regulatory molecules governing the transition from tissue injury to tissue repair, are largely unknown. NF-E2-related factor 2 (Nrf2) is a major stress-response transcription factor well known for its cell-intrinsic cytoprotective function. However, its role in cell-cell crosstalk is less appreciated. Here we report that Nrf2 is highly activated in ischemic retina and promotes revascularization by modulating neurons in their paracrine regulation of endothelial cells. Global Nrf2 deficiency strongly suppresses retinal revascularization and increases pathologic neovascularization in a mouse model of ischemic retinopathy. Conditional knockout studies demonstrate a major role for neuronal Nrf2 in vascular regrowth into avascular retina. Deletion of neuronal Nrf2 results in semaphorin 6A (Sema6A) induction in hypoxic/ischemic retinal ganglion cells in a hypoxia-inducible factor-1 alpha (HIF-1α)-dependent fashion. Sema6A expression increases in avascular inner retina and colocalizes with Nrf2 in human fetal eyes. Extracellular Sema6A leads to dose-dependent suppression of the migratory phenotype of endothelial cells through activation of Notch signaling. Lentiviral-mediated delivery of Sema6A small hairpin RNA (shRNA) abrogates the defective retinal revascularization in Nrf2-deficient mice. Importantly, pharmacologic Nrf2 activation promotes reparative angiogenesis and suppresses pathologic neovascularization. Our findings reveal a unique function of Nrf2 in reprogramming ischemic tissue toward neurovascular repair via Sema6A regulation, providing a potential therapeutic strategy for ischemic retinal and CNS diseases.
Published: 2015

20. Tissue Factor Pathway Inhibitor-2 Is Upregulated by Vascular Endothelial Growth Factor and Suppresses Growth Factor-Induced Proliferation of Endothelial Cells

Author: Elia J. Duh, Debasish Maiti, Walter Kisiel, and Zhenhua Xu
Subjects: Vascular Endothelial Growth Factor A, Interleukin-1beta, Biology, Vascular endothelial growth inhibitor, Tissue factor, Tissue factor pathway inhibitor, Cell Movement, Humans, Growth factor receptor inhibitor, RNA, Messenger, Extracellular Signal-Regulated MAP Kinases, education, Cells, Cultured, Cell Proliferation, Glycoproteins, education.field_of_study, MAP Kinase Kinase Kinases, Molecular biology, Tissue-factor-pathway inhibitor 2, Up-Regulation, Cell biology, Vascular endothelial growth factor B, Vascular endothelial growth factor A, Receptors, Vascular Endothelial Growth Factor, Gene Expression Regulation, Vascular endothelial growth factor C, Fibroblast Growth Factor 2, Endothelium, Vascular, Cardiology and Cardiovascular Medicine, Proto-Oncogene Proteins c-akt
Abstract: Objective— The purpose of this study is to investigate the expression and regulation of type-2 tissue factor pathway inhibitor (TFPI-2) in endothelial cells, as well as the regulation of human endothelial cell (EC) function by TFPI-2. Methods and Results— Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that vascular endothelial growth factor (VEGF) induced both time- and dose-dependent increase in TFPI-2 mRNA and protein expression in endothelial cells. TFPI-2 mRNA expression was also significantly upregulated by IL-1β, and modestly increased by both tumor necrosis factor (TNF)-α and fibroblast growth factor (FGF)-2, but not placental growth factor (PlGF). VEGF upregulation of TFPI-2 was dramatically reduced by inhibition of the MEK pathway. Administration of TFPI-2 protein suppressed both VEGF and FGF-2 stimulation of EC proliferation in a dose-dependent manner. A recombinant preparation of the first Kunitz-type domain of TFPI-2 (KD1) did not suppress growth factor stimulation of EC proliferation, suggesting a mechanism distinct from the proteinase inhibitory activity of TFPI-2. Exogenously added TFPI-2 protein suppressed VEGF-induced EC migration in 2 different assays. Recombinant wt-KD1 or the R24K mutant of KD1, but not the R24Q mutant, dramatically suppressed VEGF-induced EC migration. TFPI-2 protein, but not recombinant KD1, blocked VEGF-induced activation of both Akt and ERK1/2 in ECs. At higher doses, TFPI-2 protein blocked VEGFR2 activation. Conclusion— Our data suggest that VEGF-upregulation of TFPI-2 expression in endothelial cells may represent a mechanism for negative feedback regulation and modulation of its pro-angiogenic action on endothelial cells. TFPI-2, or derivatives of TFPI-2, may be novel therapeutics for treatment of angiogenic disease processes.
Published: 2006

21. Increased Expression of Iron-Regulating Genes in Monkey and Human Glaucoma

Author: Abigail S. Hackam, Itay Chowers, Mary E. Pease, Danielle Valenta, Elia J. Duh, Tushara L. Gunatilaka, Masaki Kageyama, Robert W. Nickells, Ronald H. Farkas, Harry A. Quigley, Deborah C. Otteson, Chenwei Wang, and Donald J. Zack
Subjects: Male, Pathology, medicine.medical_specialty, genetic structures, Gene Expression, Glaucoma, In situ hybridization, Retina, Immunoenzyme Techniques, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Gene expression, medicine, Animals, Humans, RNA, Messenger, In Situ Hybridization, Aged, chemistry.chemical_classification, biology, Reverse Transcriptase Polymerase Chain Reaction, Transferrin, Ceruloplasmin, Retinal, medicine.disease, Molecular biology, eye diseases, Sensory Systems, Ferritin, Reverse transcription polymerase chain reaction, Disease Models, Animal, Macaca fascicularis, Ophthalmology, chemistry, Ferritins, biology.protein, Female, sense organs
Abstract: PURPOSE. To understand the mechanisms mediating retinal ganglion cell loss in glaucoma, the gene expression patterns were compared for transferrin, ceruloplasmin, and ferritin between normal and glaucomatous retina in monkey and human eyes. METHODS. Laser photocoagulation was used to produce unilateral experimental glaucoma in monkeys. Gene expression was assessed by in situ hybridization and quantitative reverse transcription polymerase chain reaction (PCR). Immunohistochemistry was used to examine the retinal expression of iron-related proteins in the retina in experimental monkey glaucoma and human glaucoma. RESULTS. Comparison of glaucomatous with control monkey retinas demonstrated increased mRNA expression of transferrin, ceruloplasmin, and ferritin heavy and light chains. In situ hybridization localized retinal gene expression of transferrin mainly to the inner nuclear layer and ferritin to both the inner and outer nuclear layers. Immunohistochemical examination of monkey and human glaucoma for these iron-related proteins demonstrated increases at the protein level. CONCLUSIONS. Increased mRNA and protein levels of the ironregulating proteins transferrin, ceruloplasmin, and ferritin are present in glaucoma. Together, these results suggest the involvement of iron and copper metabolism and associated antioxidant systems in the pathogenesis of glaucoma. (Invest Ophthalmol Vis Sci. 2004;45:1410 –1417) DOI:10.1167/ iovs.03-0872
Published: 2004

22. Periocular injection of an adenoviral vector encoding pigment epithelium-derived factor inhibits choroidal neovascularization

Author: Elia J. Duh, T. Deering, C Cingolani, S Yamamoto, H Lai, Anna M. Demetriades, Hoseong S. Yang, Peter A. Campochiaro, Peter L. Gehlbach, and L.L. Wei
Subjects: Pathology, medicine.medical_specialty, genetic structures, Genetic enhancement, Genetic Vectors, Gene Expression, Biology, Eye, Adenoviridae, Injections, Viral vector, Neovascularization, Mice, chemistry.chemical_compound, PEDF, Genetics, medicine, Animals, Nerve Growth Factors, Eye Proteins, Molecular Biology, Serpins, Genetic transfer, Proteins, Retinal, Genetic Therapy, beta-Galactosidase, Choroidal Neovascularization, eye diseases, Sclera, Mice, Inbred C57BL, Choroidal neovascularization, medicine.anatomical_structure, chemistry, Models, Animal, Cancer research, Molecular Medicine, sense organs, medicine.symptom, Orbit
Abstract: Gene transfer provides an exciting new approach for the treatment of retinal and choroidal diseases. Two areas of concern are the potential for vector-related toxicity and uncertainties associated with prolonged transgene expression. One way to address these concerns for transfer of genes encoding secreted proteins is to transduce cells on the outside of the eye, provided the gene product can gain access to the eye and have the desired effect. In this study, we investigated the feasibility of this approach. Periocular injection of an adenoviral vector encoding beta-galactosidase (AdLacZ.10) resulted in LacZ-stained cells throughout the orbit and around the eye. Compared to periocular injection of 5 x 10(9) particles of control vector, periocular injection of 5 x 10(9) or 1 x 10(9) particles of an adenoviral vector expressing pigment epithelium-derived factor (PEDF) regulated by a CMV promoter (AdPEDF.11) resulted in significantly elevated intraocular levels of PEDF and suppression of choroidal neovascularization. Periocularly injected recombinant PEDF was also found to diffuse through the sclera into the eye. Although similar experiments are needed in an animal with a human-sized eye, these data suggest that periocular gene transfer deserves consideration for the treatment of choroidal diseases.
Published: 2003

23. Inducible Expression of Vascular Endothelial Growth Factor in Adult Mice Causes Severe Proliferative Retinopathy and Retinal Detachment

Author: Akira Hirose, Peter A. Campochiaro, D. Bok, Donald J. Zack, Michelle Chang, Naoyuki Okamoto, Sean F. Hackett, Peter L. Gehlbach, S Yamamoto, Kyoko Ohno-Matsui, Elia J. Duh, and Jina Saikia
Subjects: Vascular Endothelial Growth Factor A, Genetically modified mouse, Rhodopsin, genetic structures, Recombinant Fusion Proteins, Transgene, medicine.medical_treatment, Statistics as Topic, Mice, Transgenic, Endothelial Growth Factors, Retinal Neovascularization, Biology, Retina, Pathology and Forensic Medicine, Neovascularization, Mice, chemistry.chemical_compound, medicine, Animals, Humans, Promoter Regions, Genetic, Lymphokines, Vascular Endothelial Growth Factors, Growth factor, Retinal Detachment, Animal Models, medicine.disease, eye diseases, Anti-Bacterial Agents, Vascular endothelial growth factor, Vascular endothelial growth factor A, Phenotype, medicine.anatomical_structure, Gene Expression Regulation, chemistry, Doxycycline, Immunology, Cancer research, sense organs, medicine.symptom, Retinopathy
Abstract: Transgenic mice with vascular endothelial growth factor (VEGF) driven by the rhodopsin promoter (rho/VEGF mice) develop neovascularization that originates from the deep capillary bed of the retina and grows into the subretinal space. In rho/VEGF mice, VEGF expression in photoreceptors begins between postnatal days 5 and 7, the period when the deep capillary bed is developing. An important question is whether or not the developmental stage of the deep capillary bed is critical for occurrence of neovascularization. Also, although rho/VEGF mice are extremely useful for the study of ocular neovascularization, there are some applications for which the early onset of VEGF expression is a disadvantage. In this study, we used the reverse tetracycline transactivator (rtTA) inducible promoter system coupled to either the rhodopsin or interphotoreceptor retinoid-binding protein (IRBP) promoter to control the time of onset of VEGF transgene expression in photoreceptors. In the absence of doxycycline, adult double-transgenic rho/rtTA-TRE/VEGF or IRBP/rtTA-TRE/VEGF mice showed little VEGF transgene expression and no phenotype. The addition of doxycycline to the drinking water resulted in prominent transgene expression and evidence of neovascularization within 3 to 4 days. Like rho/VEGF mice, the neovascularization originated from the deep capillary bed of the retina, but it was more extensive and caused outer retinal folds followed by total retinal detachment. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay demonstrated that the mice with inducible expression of VEGF that developed retinal detachment had much higher ocular levels of VEGF mRNA and protein compared to rho/VEGF mice that manifest a much milder phenotype. These data demonstrate that regardless of developmental stage of the vascular bed, increased expression of VEGF in the retina is sufficient to cause neovascularization, and high levels of expression cause severe neovascularization and traction retinal detachment. Mice with inducible expression of VEGF in the retina provide a valuable new model of ocular neovascularization.
Published: 2002

24. Neuroprotective role of Nrf2 for retinal ganglion cells in ischemia-reperfusion

Author: Elia J. Duh, Hongkwan Cho, Lijuan Wu, Michael B. Sporn, Shuang Wang, Matthew J. Hartsock, Derek S. Welsbie, Katherine L. Mitchell, Junsong Gong, Yanhong Wei, Zhenhua Xu, Rajesh K. Thimmulappa, and Shyam Biswal
Subjects: Retinal Ganglion Cells, Cell Survival, NF-E2-Related Factor 2, Down-Regulation, Mice, Transgenic, Biology, In Vitro Techniques, medicine.disease_cause, Biochemistry, Retinal ganglion, Neuroprotection, digestive system, environment and public health, Retina, Article, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Mice, tert-Butylhydroperoxide, Ischemia, medicine, Animals, Viability assay, Oleanolic Acid, RNA, Small Interfering, Ganglion cell layer, Cells, Cultured, Imidazoles, Retinal, respiratory system, medicine.disease, Cell biology, Mice, Inbred C57BL, Disease Models, Animal, medicine.anatomical_structure, chemistry, Reperfusion Injury, Immunology, Reactive Oxygen Species, Reperfusion injury, Oxidative stress
Abstract: Retinal ischemia plays a critical role in multiple vision-threatening diseases and leads to death of retinal neurons, particularly ganglion cells. Oxidative stress plays an important role in this ganglion cell loss. Nrf2 (NF-E2-related factor 2) is a major regulator of the antioxidant response, and its role in the retina is increasingly appreciated. We investigated the potential retinal neuroprotective function of Nrf2 after ischemia-reperfusion (I/R) injury. In an experimental model of retinal I/R, Nrf2 knockout mice exhibited much greater loss of neuronal cells in the ganglion cell layer than wild-type mice. Primary retinal ganglion cells isolated from Nrf2 knockout mice exhibited decreased cell viability compared to wild-type retinal ganglion cells, demonstrating the cell-intrinsic protective role of Nrf2. The retinal neuronal cell line 661W exhibited reduced cell viability following siRNA-mediated knockdown of Nrf2 under conditions of oxidative stress, and this was associated with exacerbation of increase in reactive oxygen species. The synthetic triterpenoid CDDO-Im (2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide), a potent Nrf2 activator, inhibited reactive oxygen species increase in cultured 661W under oxidative stress conditions and increased neuronal cell survival after I/R injury in wild-type, but not Nrf2 knockout mice. Our findings indicate that Nrf2 exhibits a retinal neuroprotective function in I/R and suggest that pharmacologic activation of Nrf2 could be a therapeutic strategy. Oxidative stress is thought to be an important mediator of retinal ganglion cell death in ischemia-reperfusion injury. We found that the transcription factor NF-E2-related factor 2 (Nrf2), a major regulator of oxidative stress, is an important endogenous neuroprotective molecule in retinal ganglion cells in ischemia-reperfusion, exerting a cell-autonomous protective effect. The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-imidazolide (CDDO-Im) reduces neurodegeneration following ischemia-reperfusion in an Nrf2-dependent fashion. This suggests that Nrf2-activating drugs including triterpenoids could be a therapeutic strategy for retinal neuroprotection.
Published: 2014

25. Transcription Factors Sp1 and Sp3 Alter Vascular Endothelial Growth Factor Receptor Expression through a Novel Recognition Sequence

Author: Lloyd Paul Aiello, Gregory S. Robinson, Kang Zhang, Yasuaki Hata, and Elia J. Duh
Subjects: Sp1 Transcription Factor, Molecular Sequence Data, Biology, Biochemistry, Receptor tyrosine kinase, Consensus sequence, Humans, Receptors, Growth Factor, Nuclear protein, Promoter Regions, Genetic, Molecular Biology, Transcription factor, Cells, Cultured, Sp1 transcription factor, Base Sequence, Receptor Protein-Tyrosine Kinases, Zinc Fingers, Kinase insert domain receptor, Cell Biology, Oligonucleotides, Antisense, Thionucleotides, Molecular biology, DNA-Binding Proteins, Vascular endothelial growth factor A, Receptors, Vascular Endothelial Growth Factor, Sp3 Transcription Factor, Gene Expression Regulation, Protein kinase domain, biology.protein, Transcription Factors
Abstract: Kinase domain receptor (KDR) is a high affinity, endothelial cell-specific, autophosphorylating tyrosine kinase receptor for vascular endothelial growth factor. This transcriptionally regulated receptor is a critical mediator of endothelial cell (EC) growth and vascular development. In this study, we identify a DNA element modulating KDR promoter activity and evaluate the nuclear binding proteins accounting for a portion of the cell-type specificity of the region. KDR promoter luciferase activity was retained within −85/+296 and was 10–30-fold higher in EC than non-EC. Electrophoretic mobility shift assays demonstrated specific nuclear protein binding to −85/−64, and single point mutations suggested important binding nucleotides between −79/−68 with five critical bases between −74/−70 (5′-CTCCT-3′). DNA-protein complexes were displaced by Sp1 consensus sequence oligodeoxynucleotides and supershifted by Sp1- and Sp3-specific antibodies. Sp1 and Sp3 protein in EC nuclear extracts bound the −79/−68 region even when all surrounding classic Sp1 recognition sites were removed. Sp1 protein in nuclear extracts was 4–24-fold higher in EC than non-EC, whereas Sp3 was 3–7-fold higher. Sp1/Sp3 ratios in EC were 2–10-fold higher. Overexpression of Sp1 protein increased KDR promoter activity 3-fold in both EC and non-EC, whereas simultaneous co-expression of Sp3 attenuated this response. An Sp1 consensus sequence ciselement “decoy” reduced EC KDR promoter activity and mRNA expression by 85 and 69%, respectively. An antisense phosphorothioate oligodeoxynucleotide to Sp1 inhibited Sp1 and KDR protein expression by 66 and 68%, respectively, without changing Sp3 protein expression. These data illustrate that Sp1 and Sp3 modulate KDR promoter activity through a novel recognition binding sequence. However, since Sp1-mediated promoter activation is attenuated by Sp3, endothelial selective KDR promoter activity may be partially regulated by variations in the Sp1/Sp3 ratio.
Published: 1998

26. Different effects of angiopoietin‐2 in different vascular beds in the eye: new vessels are most sensitive

Author: Naoyasu Umeda, Stanley J. Wiegand, Elia J. Duh, Michele Melia, Godwin Okoye, Rajendra S. Apte, Aling Dong, Kazuki Ishibashi, Sean F. Hackett, George D. Yancopoulos, Hiroyuki Nambu, Ji Kui Shen, Sachiko Oshima, Peter A. Campochiaro, Shu Kachi, Kyoichi Takahashi, James T. Handa, Yuji Oshima, and Donald J. Zack
Subjects: Pathology, medicine.medical_specialty, genetic structures, Angiogenesis, Ischemia, Biochemistry, Neovascularization, chemistry.chemical_compound, Genetics, medicine, Molecular Biology, Retina, biology, business.industry, Retinal, Anatomy, medicine.disease, Angiopoietin receptor, eye diseases, Vascular endothelial growth factor, Choroidal neovascularization, medicine.anatomical_structure, chemistry, biology.protein, sense organs, medicine.symptom, business, Biotechnology
Abstract: In this study, we used double transgenic mice with inducible expression of angiopoietin-2 (Ang2) to investigate the role of Ang2 in the retinal and choroidal circulations and in three models of ocular neovascularization (NV). Mice with induced expression of Ang2 ubiquitously, or specifically in the retina, survived and appeared grossly normal. They also had normal-appearing retinal and choroidal circulations, demonstrating that high levels of Ang2 did not induce regression of mature retinal or choroidal vessels. When Ang2 expression was induced soon after birth, there was increased density of the deep capillary bed on postnatal day (P) 11 that returned to normal by P18, the time that retinal vascular development is usually completed. In mice with ischemic retinopathy, induction of Ang2 during the ischemic period resulted in a significant increase in retinal NV, but induction of Ang2 at a later time point when ischemia (and vascular endothelial growth factor [VEGF]) was less, hastened regression of NV. In triple transgenic mice that coexpressed VEGF and Ang2, the increased expression of Ang2 inhibited VEGF-induced NV in the retina. Increased expression of Ang2 also resulted in regression of choroidal neovascularization. These data suggest that ocular neovascularization, but not mature retinal or choroidal vessels, is sensitive to Ang2; a high Ang2/VEGF ratio promotes regression, while high Ang2 in the setting of hypoxia and/or concomitantly high Ang2 and VEGF stimulate neovascularization.
Published: 2005

27. Nrf2 acts cell-autonomously in endothelium to regulate tip cell formation and vascular branching

Author: Rajesh K. Thimmulappa, Yanhong Wei, Elia J. Duh, Beata Kosmider, Shyam Biswal, and Junsong Gong
Subjects: Vascular Endothelial Growth Factor A, Endothelium, NF-E2-Related Factor 2, Angiogenesis, Blotting, Western, Notch signaling pathway, Fluorescent Antibody Technique, Neovascularization, Physiologic, Enzyme-Linked Immunosorbent Assay, Laser Capture Microdissection, Biology, digestive system, environment and public health, Retina, Mice, Phosphatidylinositol 3-Kinases, Basic Helix-Loop-Helix Transcription Factors, medicine, Animals, Humans, Transcription factor, Protein kinase B, Adaptor Proteins, Signal Transducing, Mice, Knockout, Sprouting angiogenesis, Multidisciplinary, Receptors, Notch, Calcium-Binding Proteins, Intracellular Signaling Peptides and Proteins, Endothelial Cells, Gene Expression Regulation, Developmental, Membrane Proteins, Retinal Vessels, respiratory system, Molecular biology, Cell biology, Endothelial stem cell, Vascular endothelial growth factor A, medicine.anatomical_structure, Bromodeoxyuridine, PNAS Plus, cardiovascular system, Cryoultramicrotomy
Abstract: Angiogenesis, in which new blood vessels form via endothelial cell (EC) sprouting from existing vessels, is a critical event in embryonic development and multiple disease processes. Many insights have been made into key EC receptors and ligands/growth factors that govern sprouting angiogenesis, but intracellular molecular mechanisms of this process are not well understood. NF-E2-related factor 2 (Nrf2) is a transcription factor well-known for regulating the stress response in multiple pathologic settings, but its role in development is less appreciated. Here, we show that Nrf2 is increased and activated during vascular development. Global deletion of Nrf2 resulted in reduction of vascular density as well as EC sprouting. This was also observed with specific deletion of Nrf2 in ECs, but not with deletion of Nrf2 in the surrounding nonvascular tissue. Nrf2 deletion resulted in increased delta-like ligand 4 (Dll4) expression and Notch activity in ECs. Blockade of Dll4 or Notch signaling restored the vascular phenotype in Nrf2 KOs. Constitutive activation of endothelial Nrf2 enhanced EC sprouting and vascularization by suppression of Dll4/Notch signaling in vivo and in vitro. Nrf2 activation in ECs suppressed Dll4 expression under normoxia and hypoxia and inhibited Dll4-induced Notch signaling. Activation of Nrf2 blocked VEGF induction of VEGFR2-PI3K/Akt and downregulated HIF-2α in ECs, which may serve as important mechanisms for Nrf2 inhibition of Dll4 and Notch signaling. Our data reveal a function for Nrf2 in promoting the angiogenic sprouting phenotype in vascular ECs.
Published: 2013

28. Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4

Author: Savalan Babapoor-Farrokhran, Mahaa Umapathi, Tao Ma, Derek S. Welsbie, Shuang Wang, Jiadi Hu, Xiaoban Xin, Murilo Wendeborn Rodrigues, Gregg L. Semenza, James T. Handa, Gerard A. Lutty, Imran Ahmed Bhutto, Fabiana Kashiwabuchi, Charles G. Eberhart, Silvia Montaner, Akrit Sodhi, and Elia J. Duh
Subjects: Vascular Endothelial Growth Factor A, Angiogenesis, medicine.medical_treatment, Blotting, Western, Ischemia, Vascular permeability, Biology, Angiopoietin, Capillary Permeability, Mice, medicine, Angiopoietin-Like Protein 4, Animals, Humans, Cells, Cultured, Oligonucleotide Array Sequence Analysis, Retina, Multidisciplinary, Diabetic Retinopathy, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, medicine.disease, Hypoxia-Inducible Factor 1, alpha Subunit, Immunohistochemistry, Cell Hypoxia, Up-Regulation, Endothelial stem cell, Mice, Inbred C57BL, Vascular endothelial growth factor A, medicine.anatomical_structure, Cytokine, PNAS Plus, Immunology, Cancer research, Female, sense organs, Angiopoietins, Retinal Neurons
Abstract: Vision loss from ischemic retinopathies commonly results from the accumulation of fluid in the inner retina [macular edema (ME)]. Although the precise events that lead to the development of ME remain under debate, growing evidence supports a role for an ischemia-induced hyperpermeability state regulated, in part, by VEGF. Monthly treatment with anti-VEGF therapies is effective for the treatment of ME but results in a major improvement in vision in a minority of patients, underscoring the need to identify additional therapeutic targets. Using the oxygen-induced retinopathy mouse model for ischemic retinopathy, we provide evidence showing that hypoxic Müller cells promote vascular permeability by stabilizing hypoxia-inducible factor-1α (HIF-1α) and secreting angiogenic cytokines. Blocking HIF-1α translation with digoxin inhibits the promotion of endothelial cell permeability in vitro and retinal edema in vivo. Interestingly, Müller cells require HIF--but not VEGF--to promote vascular permeability, suggesting that other HIF-dependent factors may contribute to the development of ME. Using gene expression analysis, we identify angiopoietin-like 4 (ANGPTL4) as a cytokine up-regulated by HIF-1 in hypoxic Müller cells in vitro and the ischemic inner retina in vivo. ANGPTL4 is critical and sufficient to promote vessel permeability by hypoxic Müller cells. Immunohistochemical analysis of retinal tissue from patients with diabetic eye disease shows that HIF-1α and ANGPTL4 localize to ischemic Müller cells. Our results suggest that ANGPTL4 may play an important role in promoting vessel permeability in ischemic retinopathies and could be an important target for the treatment of ME.
Published: 2013

29. The bZIP Transcription Factor Nrl Stimulates Rhodopsin Promoter Activity in Primary Retinal Cell Cultures

Author: Donald J. Zack, David Scheurer, Qing Liang Wang, Ching-Hwa Sung, Ruben Adler, Alnawaz Rehemtulla, Rajan Kumar, Shiming Chen, Anand Swaroop, and Elia J. Duh
Subjects: Rhodopsin, Leucine zipper, genetic structures, Proto-Oncogene Proteins c-jun, Molecular Sequence Data, Response element, Chick Embryo, Regulatory Sequences, Nucleic Acid, Biology, Transfection, Biochemistry, Sequence Homology, Nucleic Acid, Gene expression, Animals, Humans, Amino Acid Sequence, Eye Proteins, Molecular Biology, Transcription factor, Cells, Cultured, Leucine Zippers, Expression vector, Base Sequence, Sequence Homology, Amino Acid, Promoter, DNA, Cell Biology, Molecular biology, DNA-Binding Proteins, Basic-Leucine Zipper Transcription Factors, Gene Expression Regulation, Regulatory sequence, biology.protein, Cattle, sense organs, Proto-Oncogene Proteins c-fos, Protein Binding, Transcription Factors
Abstract: In vitro DNA binding assays and transient transfection analysis with monkey kidney cells have implicated Nrl, a member of the Maf-Nrl subfamily of bZIP transcription factors, and the Nrl response element (NRE) in the regulation of rhodopsin expression. We have now further explored the role of the NRE and surrounding promoter elements. Using the yeast one-hybrid screen with integrated NRE and flanking DNA as bait, the predominant clone obtained was bovine Nrl. Recovery of truncated clones in the screen demonstrated that the carboxyl-terminal half of Nrl, which contains the basic and leucine zipper domains, is sufficient for DNA binding. To functionally dissect the rhodopsin promoter, transient expression studies with primary chick retinal cell cultures were performed. Deletion and mutation analyses identified two positive regulatory sequences: one between -40 and -84 base pairs (bp) and another between -84 and -130 bp. Activity of the -40 to -84 region was shown to be largely due to the NRE. On co-transfection with an NRL expression vector, there were 3-5-fold increases in the activity of rhodopsin promoter constructs containing an intact NRE but little or no effect with rhodopsin promoters containing a mutated or deleted NRE. Nrl was more effective than the related bZIP proteins, c-Fos and c-Jun, in stimulating rhodopsin promoter activity. The -84- to -130-bp region acted synergistically with the NRE to enhance both the level of basal expression and the degree of Nrl-mediated trans-activation. These studies support Nrl as a regulator of rhodopsin expression in vivo, identify an additional regulatory region just upstream of the NRE, and demonstrate the utility of primary retinal cell cultures for characterizing both the cis-acting response elements and trans-acting factors that regulate photoreceptor gene expression.
Published: 1996

30. Use of a Marked Erythropoietin Gene for Investigation of Its Cis-acting Elements

Author: Elia J. Duh, Vincent T. Ho, H. Franklin Bunn, and Anthony Acquaviva
Subjects: Reporter gene, Messenger RNA, Base Sequence, Molecular Sequence Data, Endogeny, DNA, Cell Biology, Transfection, Biology, Polymerase Chain Reaction, Biochemistry, Molecular biology, Cell Line, Exon, Erythropoietin, hemic and lymphatic diseases, medicine, Humans, RNA, Messenger, Enhancer, Molecular Biology, Gene, medicine.drug
Abstract: To examine the function of conserved noncoding regions in the erythropoietin (Epo) gene, we have prepared clones and pools of Hep3B cells stably transfected with a marked 4.1-kilobase Epo gene and deletions thereof. The marked transcripts had single base substitutions at three sites in the coding portion of Exon 5, enabling them to be distinguished from endogenous Epo mRNA by ribonuclease protection and competitive polymerase chain reaction. The basal expression and hypoxic induction of the marked Epo gene that had no deletions were indistinguishable from that of the endogenous Epo gene. Likewise, deletion of conserved intervening sequence 1 had minimal effect on hypoxic induction. In contrast, a 3′-deletion that included the conserved 3′-enhancer element resulted in a substantial, but not complete, suppression of hypoxic induction while a 3′-deletion downstream of the enhancer resulted in enhancement. A 188-base pair deletion of a conserved 3′-untranslated region in Exon 5 had minimal effect on hypoxic induction. However, the truncated Epo mRNA had a markedly prolonged half-life (15 h) in comparison to the endogenous Epo mRNA (2.0 h) or the marked full-length Epo mRNA (2.1 h). Further deletions in the 3′-UTR showed that a relatively small region of approximately 50 bases is responsible for the relatively rapid turnover of Epo mRNA. These experiments provide information on cis-acting elements of the Epo gene that cannot be obtained from conventional reporter gene transfection experiments.
Published: 1995

31. Novel targets against retinal angiogenesis in diabetic retinopathy

Author: Elia J. Duh, Shuang Wang, and James K. Park
Subjects: Male, Vascular Endothelial Growth Factor A, Angiogenesis, Endocrinology, Diabetes and Metabolism, Integrin, Angiogenesis Inhibitors, Retinal Neovascularization, Blindness, Macular Edema, chemistry.chemical_compound, Internal Medicine, medicine, Humans, Erythropoietin, Diabetic Retinopathy, biology, business.industry, Retinal, Diabetic retinopathy, medicine.disease, Vascular endothelial growth factor, Vascular endothelial growth factor A, chemistry, Hyperglycemia, Immunology, biology.protein, Cancer research, Molecular targets, Disease Progression, Female, business
Abstract: Proliferative diabetic retinopathy (PDR), characterized by pathologic retinal angiogenesis, is a major cause of blindness in the USA and globally. Treatments targeting vascular endothelial growth factor (VEGF) have emerged as a beneficial part of the therapeutic armamentarium for this condition, highlighting the utility of identifying and targeting specific pathogenic molecules. There continues to be active research into the molecular players regulating retinal angiogenesis, including pro-angiogenic factors, anti-angiogenic factors, and integrins and matrix proteinases. New insights have been especially prominent regarding molecules which regulate specialized endothelial cells called tip cells, which play a lead role in endothelial sprouting. Together, these research efforts are uncovering new, important molecular regulators of retinal angiogenesis, which provide fertile areas for therapeutic exploration. This review discusses potential molecular targets, with an emphasis towards newer targets.
Published: 2012

32. Pigment epithelium-derived factor regulates lipid metabolism via adipose triglyceride lipase

Author: Elia J. Duh, Matthew J. Watt, Rudolf Zechner, Peter J. Meikle, Zane B. Andrews, and Melissa L. Borg
Subjects: medicine.medical_specialty, Spectrometry, Mass, Electrospray Ionization, Endocrinology, Diabetes and Metabolism, Lipolysis, Immunoblotting, Fluorescent Antibody Technique, Hormone-sensitive lipase, Carbohydrate metabolism, Biology, Cell Line, chemistry.chemical_compound, Mice, Internal medicine, 3T3-L1 Cells, Internal Medicine, medicine, Animals, Nerve Growth Factors, Eye Proteins, Serpins, chemistry.chemical_classification, Fatty acid metabolism, Triglyceride, Reverse Transcriptase Polymerase Chain Reaction, Fatty Acids, Fatty acid, Lipid metabolism, Lipase, Lipid Metabolism, Mice, Mutant Strains, Endocrinology, Glucose, Metabolism, chemistry, Adipose Tissue, Adipose triglyceride lipase
Abstract: OBJECTIVE Pigment epithelium–derived factor (PEDF) is an adipocyte-secreted factor involved in the development of insulin resistance in obesity. Previous studies have identified PEDF as a regulator of triacylglycerol metabolism in the liver that may act through adipose triglyceride lipase (ATGL). We used ATGL−/− mice to determine the role of PEDF in regulating lipid and glucose metabolism. RESEARCH DESIGN AND METHODS Recombinant PEDF was administered to ATGL−/− and wild-type mice, and whole-body energy metabolism was studied by indirect calorimetry. Adipose tissue lipolysis and skeletal muscle fatty acid metabolism was determined in isolated tissue preparations. Muscle lipids were assessed by electrospray ionization–tandem mass spectrometry. Whole-body insulin sensitivity and skeletal muscle glucose uptake were assessed. RESULTS PEDF impaired the capacity to adjust substrate selection, resulting in a delayed diurnal decline in the respiratory exchange ratio, and suppressed daily fatty acid oxidation. PEDF enhanced adipocyte lipolysis and triacylglycerol lipase activity in skeletal muscle. Muscle fatty acid uptake and storage were unaffected, whereas fatty acid oxidation was impaired. These changes in lipid metabolism were abrogated in ATGL−/− mice and were not attributable to hypothalamic actions. ATGL−/− mice were also refractory to PEDF-mediated insulin resistance, but this was not related to changes in lipid species in skeletal muscle. CONCLUSIONS The results are the first direct demonstration that 1) PEDF influences systemic fatty acid metabolism by promoting lipolysis in an ATGL-dependent manner and reducing fatty acid oxidation and 2) ATGL is required for the negative effects of PEDF on insulin action.
Published: 2011

33. Antipermeability Function of PEDF Involves Blockade of the MAP Kinase/GSK/β-Catenin Signaling Pathway and uPAR Expression

Author: Ruth B. Caldwell, Elia J. Duh, Jinling Yang, and M. Ali Behzadian
Subjects: Vascular Endothelial Growth Factor A, Blotting, Western, Biology, Receptors, Urokinase Plasminogen Activator, Capillary Permeability, Glycogen Synthase Kinase 3, PEDF, GSK-3, Electric Impedance, Animals, Nerve Growth Factors, Enzyme Inhibitors, Phosphorylation, Protein kinase A, Eye Proteins, Serpins, beta Catenin, MAPK14, Glycogen Synthase Kinase 3 beta, Microscopy, Confocal, MAP kinase kinase kinase, Reverse Transcriptase Polymerase Chain Reaction, Retinal Vessels, Dextrans, Articles, Molecular biology, Immunohistochemistry, Cell biology, Urokinase receptor, Vascular endothelial growth factor A, Cattle, Endothelium, Vascular, Signal transduction, Mitogen-Activated Protein Kinases, Fluorescein-5-isothiocyanate, Signal Transduction
Abstract: Pigment epithelium–derived factor (PEDF) is a 50-kDa glycoprotein expressed in many cell types, including retinal pigment epithelial cells, vascular endothelial cells, and pericytes. It was first identified as a neurotrophic factor1 and was later found to have antipermeability activity.2 Patients with diabetic macular edema have been shown to have elevated VEGF and reduced PEDF levels in ocular tissue, suggesting that a balance between PEDF and VEGF is critical for preserving the blood–retinal barrier.3,4 PEDF has been shown to block retinal vascular permeability increases induced by VEGF, advanced glycation end products, and diabetic conditions.2,5,6 It also prevents retinal pigmented epithelium barrier dysfunction after oxidant treatment.7 Despite all the information available about the beneficial effects of PEDF, the mechanism of its protective action on blood–retinal barrier function is still not clear. It has been shown that VEGF induces hyperpermeability of endothelial cell monolayers by activating the uPA/uPAR system (urokinase and its receptor) through transcriptional activation of β-catenin, thus increasing uPAR expression.8 The increase in uPAR expression in the retina has also been confirmed in a diabetic animal model.9 uPA is a serine protease that can be activated by binding to uPAR and catalyzes conversion of plasminogen to plasmin, which can degrade the extracellular matrix, activate latent growth factors such as TGF-β, and convert inactive–matrix metalloproteinase (pro-MMPs), including MMP-2 and -9, into their active forms.10 Furthermore, a pharmacologic inhibitor of the uPA/uPAR system has been reported to inhibit alteration of the blood–retinal barrier in a diabetic animal model.11 β-Catenin is a component of the adherens junction complex. It links the intracellular domain of cadherin to actin filaments, the main component of the cytoskeleton. Under normal conditions, free β-catenin released from the junction complex is phosphorylated by binding to glycogen synthase kinase 3 (GSK3)-β and is targeted for ubiquitination and degradation.12 Under certain stimulations, β-catenin escapes phosphorylation and degradation, accumulates in the cytosol, and translocates to the nucleus. In the nucleus, β-catenin acts as a transcription factor and works with other transcription factors such as T-cell factor/lymphoid-enhancing factor (TCF/LEF) to induce expression of uPAR.13 Mitogen-activated protein (MAP) kinases are serine/threonine-specific protein kinases that regulate gene expression and cell proliferation, differentiation, and survival. Two MAP kinase subtypes, p38 MAP kinase and extracellular signal–regulated protein kinase (ERK), are important regulators of endothelial cell proliferation and migration and are activated in endothelial cells treated with VEGF.14 Activation of p38 MAP kinase has also been reported in endothelial cells maintained in high glucose in vitro15 and in diabetic retinas in vivo.16 In general, p38 MAP kinase has been designated as stress-activated kinase and is known to block cell proliferation and to induce apoptosis in a variety of cell types.17,18 On the other hand, ERK1/2 kinase is mostly activated in response to mitogenic stimuli and has been associated with cell proliferation. However, ERK1/2 may cross-talk with the p38 activation pathway under certain inflammatory conditions.19 Both p38 MAP kinase and ERK have been shown to play a critical role in activation of the uPA/uPAR system.20–22 The purpose of this study was to identify upstream mediators in VEGF-induced activation of the β-catenin–uPA/uPAR permeability pathway and to examine whether PEDF preserves the barrier function by blocking this pathway.
Published: 2010

34. Variable role of the long terminal repeat Sp1-binding sites in human immunodeficiency virus replication in T lymphocytes

Author: Elia J. Duh, Malcolm A. Martin, John P. Leonard, Alicia Buckler-White, Theodore S. Theodore, Todd Seidner, Arnold B. Rabson, and Carmen Parrott
Subjects: Sp1 Transcription Factor, T-Lymphocytes, medicine.medical_treatment, Molecular Sequence Data, Restriction Mapping, Immunology, Biology, Virus Replication, Microbiology, Virus, Cell Line, Virology, medicine, Animals, HIV Long Terminal Repeat, Binding Sites, Base Sequence, NF-kappa B, HIV, Molecular biology, Long terminal repeat, Kinetics, Cytokine, Viral replication, Cell culture, Insect Science, Mutagenesis, Site-Directed, Tumor necrosis factor alpha, Chromosome Deletion, Clone (B-cell biology), Transcription Factors, Research Article
Abstract: The long terminal repeat (LTR) of the human immunodeficiency virus (HIV) contains three binding sites for the transcriptional factor Sp1. In order to investigate the role that the Sp1-binding sites play in regulation of HIV replication, we have introduced a deletion of all three Sp1-binding sites into the LTR of an infectious molecular clone of HIV. Viral stocks have been prepared from this mutant virus, designated dl-Sp, and these stocks have been used to study its replicative ability in human T cells. The dl-Sp virus replicated efficiently in MT4 cells and in phytohemagglutinin-stimulated human peripheral blood lymphocytes, but it replicated poorly and with delayed kinetics in A3.01 (CEM) T cells unless those cells had been treated with the cytokine tumor necrosis factor alpha. Gel retardation assays to study the levels of DNA-binding proteins present in these cells showed that NF-kappa B activity could be detected in the nuclei of MT4 cells but not in A3.01 cells unless they had been treated with tumor necrosis factor alpha. Thus, the presence of NF-kappa B activity appeared to be required for efficient replication of an HIV whose LTR Sp1-binding sites had been deleted. This suggests that NF-kappa B can functionally compensate for Sp1 in activating HIV replication. The HIV LTR is therefore similar to the promoter-enhancer units of other viruses in that it is composed of multiple functional elements that may contribute differently to viral replication depending on the levels of DNA-binding proteins present in the target cells.
Published: 1991

35. Vascular endothelial growth factor induces MEF2C and MEF2-dependent activity in endothelial cells

Author: Elia J. Duh, Debasish Maiti, and Zhenhua Xu
Subjects: Vascular Endothelial Growth Factor A, Umbilical Veins, Time Factors, Angiogenesis, Blotting, Western, Cell Culture Techniques, MADS Domain Proteins, Biology, Transfection, Article, chemistry.chemical_compound, Vasculogenesis, Cell Movement, Humans, RNA, Messenger, S1PR1, Protein Kinase C, Dose-Response Relationship, Drug, MEF2 Transcription Factors, Reverse Transcriptase Polymerase Chain Reaction, ETS transcription factor family, Retinal Vessels, Recombinant Proteins, Up-Regulation, Vascular endothelial growth factor B, Vascular endothelial growth factor, Vascular endothelial growth factor A, Vascular endothelial growth factor C, chemistry, Gene Expression Regulation, Myogenic Regulatory Factors, Cancer research, Endothelium, Vascular, Plasmids
Abstract: Vascular endothelial growth factor (VEGF, also referred to as VEGF-A) is a key regulator in physiological angiogenesis and in pathologic angiogenic processes, such as those associated with tumor growth and retinal neovascularization.1 The proangiogenic activity of VEGF derives from its ability to regulate many steps in the angiogenic process, including proliferation, migration, survival, and permeability. Much is known about the upstream events mediating the effect of VEGF on endothelial cells, including the major signaling pathways that are activated.2–4 Relatively less is known about the key transcription factors involved in the angiogenic effects of VEGF. The myocyte enhancer factor (MEF)-2 family of transcription factors consists of a group of transcriptional activators (MEF2A, -B, -C, and -D) that show homology in a MADS (MCM1, Agamous, Deficiens, serum response factor) box and an adjacent motif known as the MEF2 domain.5 MEF2 factors play a pivotal role in the morphogenesis and myogenesis of skeletal, cardiac, and smooth muscle cells.6 Of the MEF2 family members, MEF2C appears to have a particularly important role in vasculogenesis and angiogenesis during vascular development. MEF2C is expressed in endothelial cells in vivo7 and in vitro.8 Targeted deletion of the MEF2C gene in mice results in embryonic lethality between embryonic day (E) 9.5 and E10,7,9 with significant cardiovascular defects.7,10 These mice exhibit severe vascular abnormalities, including the absence of yolk sac vascularization.7 In these mice, endothelial cells are able to differentiate but are unable to become organized into a vascular network.7 The overall phenotype of MEF2C mutant mice is similar to that of mice lacking VEGF or Flt-1.7 MEF2C appears to be a direct transcriptional target of Ets transcription factors in the developing and the adult vasculature. A transcriptional enhancer from the MEF2C gene containing four consensus Ets transcription factor binding sites is sufficient to direct gene expression to the vascular endothelium in developing and adult vasculature in transgenic LacZ reporter mice.11 The regulation of MEF2C gene expression by Ets transcription factors is of particular interest because VEGF is known to upregulate Ets-1 in endothelial cells.12 In light of the important role of MEF2C in vasculogenesis and angiogenesis, we were interested in characterizing the regulation of MEF2C by VEGF and the potential role of MEF2 in endothelial cells. We found that VEGF induces MEF2C gene expression in a protein kinase C–dependent manner. In addition, VEGF activates MEF2-dependent transcription, and this activation is regulated by several signaling pathways. Finally, MEF2C may play an important role in endothelial cell migration.
Published: 2008

36. Renaming the DSCR1/Adapt78 gene family as RCAN: regulators of calcineurin

Author: Jeffery D. Molkentin, Melanie April Pritchard, Joseph Heitman, Lois J. Maltais, Zhuohua Zhang, Joohong Ahnn, Dana R. Crawford, Mercè Pérez-Riba, Paolo Carinci, Gennady Ermak, Martha S. Cyert, Kelvin J.A. Davies, Kyle W. Cunningham, Eric N. Olson, Claude B. Klee, Juan Miguel Redondo, Hisao Seo, R. Sanders Williams, Flávio Henrique-Silva, Kyung-Tai Min, Hans-Peter Gerber, Pierluigi Strippoli, Silvia Canaider, Sue Povey, Xia Cao, Elia J. Duh, Beverley A. Rothermel, Elspeth A. Bruford, Gerald R. Crabtree, Deborah S. Fox, Rhonda S Bassel-Duby, Susana de la Luna, Xavier Estivill, and Frank McKeon
Subjects: Calcineurin, Calcineurin Inhibitors, Intracellular Signaling Peptides and Proteins, Muscle Proteins, Biology, Biochemistry, Cell biology, DNA-Binding Proteins, Isoenzymes, Multigene Family, Genetics, Animals, Humans, Down Syndrome, Molecular Biology, Humanities, Biotechnology
Abstract: Kelvin J. A. Davies,* Gennady Ermak,* Beverley A. Rothermel, Melanie Pritchard, Joseph Heitman, Joohong Ahnn, Flavio Henrique-Silva, Dana Crawford, Silvia Canaider,** Pierluigi Strippoli,** Paolo Carinci,** Kyung-Tai Min, Deborah S. Fox, Kyle W. Cunningham, Rhonda Bassel-Duby, Eric N. Olson, Zhuohua Zhang, R. Sanders Williams, Hans-Peter Gerber,*** Merce Perez-Riba, Hisao Seo, Xia Cao, Claude B. Klee, Juan Miguel Redondo, Lois J. Maltais, Elspeth A. Bruford, Sue Povey, Jeffery D. Molkentin,**** Frank D. McKeon, Elia J. Duh, Gerald R. Crabtree,§§§§ Martha S. Cyert, Susana de la Luna, and Xavier Estivill
Published: 2007

37. Vascular endothelial growth factor upregulates expression of ADAMTS1 in endothelial cells through protein kinase C signaling

Author: Elia J. Duh, Zhenhua Xu, and Yilin Yu
Subjects: Vascular Endothelial Growth Factor A, Time Factors, Endothelium, Angiogenesis, Blotting, Western, Biology, Retinal Neovascularization, Vascular endothelial growth inhibitor, chemistry.chemical_compound, Mice, ADAMTS1 Protein, medicine, Animals, Humans, RNA, Messenger, Cells, Cultured, Protein Kinase C, Dose-Response Relationship, Drug, Reverse Transcriptase Polymerase Chain Reaction, Retinal Vessels, Recombinant Proteins, Up-Regulation, Vascular endothelial growth factor, Endothelial stem cell, Vascular endothelial growth factor B, Mice, Inbred C57BL, Oxygen, Vascular endothelial growth factor A, ADAM Proteins, medicine.anatomical_structure, Vascular endothelial growth factor C, chemistry, Gene Expression Regulation, Cancer research, Endothelium, Vascular, Signal Transduction
Abstract: Purpose ADAMTS1 (a disintegrin and metalloproteinase with thrombospondin motifs) has been demonstrated to inhibit angiogenesis in vivo and to suppress endothelial cell proliferation in vitro. The purpose of this study was to investigate the expression of ADAMTS1 in endothelial cells and in a mouse model of ischemia-induced retinal neovascularization and to study the regulation of ADAMTS1 expression in endothelial cells by vascular endothelial growth factor (VEGF). In addition, the potential function of endothelial cell-derived ADAMTS1 on cell proliferation was investigated. Methods Expression of ADAMTS1 in human retinal endothelial cells (HRECs), human umbilical vein endothelial cells (HUVECs), and the mouse model of ischemia-induced retinal neovascularization was assayed by real-time PCR and Western blot analysis. The effect of ADAMTS1 on endothelial cell proliferation was evaluated using siRNA knockdown and [3H] thymidine incorporation. Results ADAMTS1 mRNA and protein levels were increased in a mouse model of ischemia-induced retinal neovascularization, and VEGF induced time- and dose-dependent increases in ADAMTS1 mRNA and protein expression in endothelial cells. This upregulation was inhibited by the VEGF receptor (VEGFR)2 inhibitor SU1498, anti-VEGFR2 neutralizing antibody, and the phospholipase C (PLC)-gamma inhibitor U73122. VEGF upregulation of ADAMTS1 expression was completely abolished by the inhibition of protein kinase C by calphostin C and largely blocked by the specific inhibition of PKCbeta. Knockdown of endogenous ADAMTS1 resulted in increased proliferation of endothelial cells. Conclusions These results indicate that VEGF significantly induces ADAMTS1 expression in endothelial cells in a PKC-dependent fashion. ADAMTS1 expression is also increased, along with VEGF expression, in vivo in ischemia-induced retinal neovascularization. In addition, ADAMTS1 appears to be an endogenous regulator of endothelial cell proliferation. Therefore, VEGF upregulation of ADAMTS1, a potent angiogenesis inhibitor, may represent a mechanism for feedback inhibition of angiogenesis and retinal neovascularization.
Published: 2006

38. A system for inducible gene expression in retinal ganglion cells

Author: Yilin Yu, Deborah C. Otteson, John B. Kerrison, Elia J. Duh, and Donald J. Zack
Subjects: Retinal Ganglion Cells, Transcriptional Activation, Genotype, Transgene, Mice, Transgenic, Biology, Retinal ganglion, Mice, PEDF, Gene expression, medicine, Animals, Nerve Growth Factors, Eye Proteins, Promoter Regions, Genetic, Serpins, Regulation of gene expression, Retina, beta-Galactosidase, Molecular biology, Mice, Inbred C57BL, Proto-Oncogene Proteins c-kit, medicine.anatomical_structure, Retinal ganglion cell, Gene Expression Regulation, Lac Operon, Tetracyclines, Doxycycline, Inner nuclear layer, Trans-Activators, Thy-1 Antigens, sense organs
Abstract: Purpose To develop a system for inducible gene expression in retinal ganglion cells, Thy1 and ckit promoters were used to direct expression of a second-generation reverse tetracycline transactivator (rtTA2S-M2). Methods Transgenic mice were generated that harbor rtTA2S-M2 under the control of either the Thy1 or ckit promoter. These animals were crossed with mice transgenic for the LacZ gene downstream of a cassette of tet operator (TRE) binding sites. Induction of the LacZ reporter gene in vivo after either oral or subcutaneous doxycycline administration and in vitro in cultured retinal cells was assessed. To examine induction of a secreted protein, expression of pigment epithelium-derived factor (PEDF) in mice harboring Thy1-rtTA and TRE-PEDF constructs was quantified. Results Five of seven Thy1-rtTA lines showed induction with subcutaneous doxycycline: maximum induction in one line (Thy1-C), moderate in one line (Thy1-F), and minimal in three lines. There was no detectable retinal LacZ expression in the ckit-rtTA lines, despite expression of the ckit-rtTA transgene at the RNA level. In Thy1-rtTA lines, LacZ reporter expression as measured by X-gal staining was evenly dispersed throughout all quadrants of the retina, present in a subpopulation of retinal ganglion cell (RGC) bodies, RGC axons projecting through the retina and optic nerve, and some cells in the inner nuclear layer. Immunostaining for beta-galactosidase demonstrated more uniform expression in RGCs and cells of the inner aspect of the inner nuclear layer, which, by double staining with anti-beta-galactosidase and anti-calretinin antibodies, were consistent with amacrine cells. More than 95% of Thy-1 antigen-positive cells in the retina expressed the induced transgene. Subcutaneous doxycycline resulted in a more robust induction of LacZ than did oral administration. In vitro, the number of cells induced in culture increased in a dose-dependent manner, with maximum expression at 10 microg/mL at a level 3.4-fold over background. Thy1-rtTA/TRE-PEDF mice treated with doxycycline had 1000-fold induction in their retinal PEDF expression in comparison with nontransgenic mice and 600-fold induction over noninduced Thy1-rtTA/TRE-PEDF mice. Conclusions A transgenic system for inducible RGC expression has been developed that demonstrates minimal leakiness and significant induction with doxycycline. This system will be useful for several applications.
Published: 2005

39. VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis?

Author: Elia J. Duh and Yong-Gang Yao
Subjects: Vascular Endothelial Growth Factor A, Angiogenesis, Calcineurin Inhibitors, Biophysics, Regulator, Muscle Proteins, Neovascularization, Physiologic, Biology, Biochemistry, Genes, Reporter, Gene expression, Humans, Protein Isoforms, RNA, Messenger, Enzyme Inhibitors, Promoter Regions, Genetic, Molecular Biology, Protein kinase C, Calcimycin, Cells, Cultured, Regulation of gene expression, Feedback, Physiological, Reporter gene, Ionophores, NFATC Transcription Factors, Tumor Necrosis Factor-alpha, Calcineurin, Intracellular Signaling Peptides and Proteins, Endothelial Cells, Membrane Proteins, Nuclear Proteins, Cell Biology, Cell biology, Endothelial stem cell, DNA-Binding Proteins, Isoenzymes, Gene Expression Regulation, Cyclooxygenase 2, Prostaglandin-Endoperoxide Synthases, Cancer research, Endothelium, Vascular, Signal transduction, Down Syndrome, Signal Transduction, Transcription Factors
Abstract: The Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-alpha, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca(2+) chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells.
Published: 2004

40. Retinal neuroprotection against ischemic injury mediated by intraocular gene transfer of pigment epithelium-derived factor

Author: Elia J. Duh, Keisuke Mori, Shin Yoneya, Lisa L. Wei, Peter L. Gehlbach, and Hiroyasu Takita
Subjects: Retinal Ganglion Cells, medicine.medical_specialty, genetic structures, Cell Survival, Genetic Vectors, Apoptosis, Cell Count, Enzyme-Linked Immunosorbent Assay, Biology, Adenoviridae, chemistry.chemical_compound, PEDF, Retinal Diseases, Ophthalmology, medicine, In Situ Nick-End Labeling, Animals, Nerve Growth Factors, Outer nuclear layer, Eye Proteins, Ganglion cell layer, Serpins, Retina, TUNEL assay, Genetic transfer, Gene Transfer Techniques, Proteins, Retinal, Anatomy, Genetic Therapy, eye diseases, Rats, medicine.anatomical_structure, chemistry, Cytoprotection, Rats, Inbred Lew, Reperfusion Injury, Inner nuclear layer, Female, sense organs
Abstract: PURPOSE. To determine whether intraocular gene transfer of pigment epithelium-derived factor (PEDF) protects the retina from ischemia-reperfusion injury. METHODS. Four days before induction of pressure-induced ischemia, Lewis rats received intravitreous injection of 3 X 10 9 particles of an adenovirus vector expressing PEDF (AdPEDF.11) in one eye and 3 X 10 9 particles of an empty adenovirus vector (AdNull.11) in the contralateral eye. Seven days after reperfusion, eyes were enucleated and processed for morphometric analysis. Apoptotic cells stained by TdT-dUTP terminal nick-end labeling (TUNEL) in the retina were counted 12 hours after initiation of reperfusion. Retina levels of PEDF were measured by enzyme-linked immunosorbent assay. RESULTS. PEDF levels in retinal homogenates from eyes receiving AdPEDF.11 injection were well above the background levels in the untreated baseline and control eyes (P = 0.04). Retinal thickness was preserved in AdPEDF. 11-treated eyes. Retinal cell density was significantly greater in the ganglion cell layer (GCL; P = 0.014), inner nuclear layer (INL; P = 0.008), and outer nuclear layer (ONL; P = 0.008) of AdPEDF.11-treated eyes compared with the corresponding layers in AdNull.11-treated eyes. AdNull.11-treated eyes also had significantly more TUNEL-positive cells in these layers than AdPEDF. 11-treated eyes (P < 0.05). CONCLUSIONS. Adenoviral vector-mediated intraocular expression of PEDF significantly increases cell survival after ischemia-reperfusion injury of the retina. The protective effect may result from inhibition of ischemia-induced apoptosis. This study provides proof of concept for a gene transfer approach directed at interrupting programmed cell death induced by retinal ischemic insult.
Published: 2003

41. Sema 3A resists retinal revascularization

Author: Elia J. Duh
Subjects: Retina, Pathology, medicine.medical_specialty, genetic structures, medicine.medical_treatment, Regeneration (biology), Immunology, Retinal, SEMA3A, Cell Biology, Hematology, Anatomy, Biology, Revascularization, Biochemistry, eye diseases, chemistry.chemical_compound, medicine.anatomical_structure, nervous system, chemistry, Semaphorin, medicine, sense organs, Avascular retina
Abstract: In this issue of Blood , Joyal and colleagues make the insightful finding that Semaphorin 3A (Sema3A) is secreted by hypoxic neurons in ischemic/avascular retina, thereby inhibiting vascular regeneration of the retina and enhancing pathologic preretinal neovascularization.[1][1] Ischemic
Published: 2011

42. TNFα Is Required for Late BRB Breakdown in Diabetic Retinopathy, and Its Inhibition Prevents Leukostasis and Protects Vessels and Neurons from Apoptosis

Author: Jarel K. Gandhi, Junsong Gong, Xiufeng Zhong, Elia J. Duh, Hu Huang, Yanhong Wei, and Stanley A. Vinores
Subjects: Male, medicine.medical_specialty, Genotype, Cell Survival, Blood–retinal barrier, Apoptosis, Enzyme-Linked Immunosorbent Assay, Inflammation, Vascular permeability, Caspase 3, Biology, Diabetes Mellitus, Experimental, Capillary Permeability, Mice, Internal medicine, Blood-Retinal Barrier, In Situ Nick-End Labeling, medicine, Animals, Gene Silencing, Fluorescent Antibody Technique, Indirect, Mice, Knockout, Diabetic Retinopathy, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Retinal Vessels, Leukostasis, Articles, Diabetic retinopathy, medicine.disease, Actins, Mice, Inbred C57BL, Platelet Endothelial Cell Adhesion Molecule-1, Endocrinology, medicine.anatomical_structure, Female, Tumor necrosis factor alpha, sense organs, medicine.symptom, Retinal Neurons
Abstract: Blood-retinal barrier [BRB] breakdown, characteristic of diabetic retinopathy (DR), is believed to depend on inflammation and apoptosis. Retinal inflammation is almost completely suppressed in the absence of TNFα, which is also associated with apoptosis. This study was conducted to determine the role of TNFα in these diabetic complications.Diabetes was induced with streptozotocin in Tnfa knockout (KO) mice, to provide a chemical model of diabetes, and Tnfa (KO) mice were crossed with Ins2(Akita) mice to generate a genetic model, with both models being devoid of TNFα. The BRB was assessed at 1, 1.5, 3, and 6 months. Leukostasis was assessed using FITC-conjugated ConA to label leukocytes. Apoptosis was assessed with TUNEL and activated caspase-3 staining. PECAM1 identified endothelial cells, and SMA identified pericytes.At 1 month of diabetes, the absence of TNFα had no effect on DR-associated BRB breakdown, even though it prevented retinal leukostasis, demonstrating that neither TNFα nor inflammation is essential for early BRB breakdown in DR in either model of diabetes. At 3 months of diabetes, BRB breakdown was significantly suppressed and at 6 months, it was completely prevented in the absence of TNFα in both models, showing that TNFα is essential for progressive BRB breakdown. DR-mediated apoptosis in the retina, which appears to involve endothelial cells, pericytes, and neurons, was inhibited in the absence of TNFα in both models.Although neither TNFα nor inflammation is necessary for early BRB breakdown in DR, TNFα is critical for later complications and would be a good therapeutic target for the prevention of the progressive BRB breakdown, retinal leukostasis, and apoptosis associated with DR.
Published: 2011

43. Interleukin 6 induces human immunodeficiency virus expression in infected monocytic cells alone and in synergy with tumor necrosis factor alpha by transcriptional and post-transcriptional mechanisms

Author: Peter Bressler, Alan S. Rabson, Jesse S. Justement, Sharilyn K. Stanley, Elia J. Duh, W C Timmer, Guido Poli, Audrey Kinter, Anthony S. Fauci, Poli, Guido, Bressler, P, Kinter, A, Duh, E, Timmer W., C, Rabson, A, Justement J., S, Stanley, S, and Fauci, A. S.
Subjects: Gene Expression Regulation, Viral, Transcription, Genetic, medicine.medical_treatment, Immunology, Blotting, Western, Retroviridae Proteins, Biology, Monocytes, Cell Line, Downregulation and upregulation, Colony-Stimulating Factors, Transcription (biology), medicine, Immunology and Allergy, Humans, Interleukin 6, Growth Substances, Regulation of gene expression, Interleukin-6, Tumor Necrosis Factor-alpha, RNA, virus diseases, Granulocyte-Macrophage Colony-Stimulating Factor, Drug Synergism, Articles, Blotting, Northern, Virology, Recombinant Proteins, Granulocyte macrophage colony-stimulating factor, Cytokine, biology.protein, HIV-1, RNA, Viral, Tumor necrosis factor alpha, Virus Activation, medicine.drug
Abstract: The immunoregulatory cytokine interleukin 6 (IL-6) directly upregulates production of human immunodeficiency virus (HIV) in acutely as well as in chronically infected cells of monocytic lineage. In addition, IL-6 synergizes with tumor necrosis factor alpha (TNF-alpha) in the induction of latent HIV expression. Unlike TNF-alpha, upregulation of viral expression induced by IL-6 alone does not occur at the transcriptional level and it is not associated with accumulation of HIV RNA. However, when IL-6 and TNF-alpha synergistically stimulate HIV production, accumulation of HIV RNA and increased transcription are observed, indicating that IL-6 affects HIV expression at multiple (transcriptional and post-transcriptional) levels.
Published: 1990

44. Identification of Novel Genes Preferentially Expressed in the Retina Using a Custom Human Retina cDNA Microarray

Author: Peter A. Campochiaro, Elia J. Duh, Chenwei Wang, Jiang Qian, Ronald H. Farkas, Itay Chowers, Tushara L. Gunatilaka, Masaaki Kageyama, Amit Vora, Donald J. Zack, and Abigail S. Hackam
Subjects: Adult, Male, Databases, Factual, Microarray, Gene Expression, Biology, Polymerase Chain Reaction, Retina, Sequence-tagged site, Complementary DNA, Gene expression, medicine, Humans, Eye Proteins, Gene, Aged, Oligonucleotide Array Sequence Analysis, Sequence Tagged Sites, Aged, 80 and over, Expressed Sequence Tags, Genetics, Expressed sequence tag, Gene Expression Profiling, Middle Aged, Gene expression profiling, medicine.anatomical_structure, Female, sense organs
Abstract: Purpose To construct a custom cDNA microarray for comprehensive human retinal gene expression profiling and apply it to the identification of genes that are preferentially expressed in the retina. Methods A cDNA microarray was constructed based on the predicted human retina gene expression profile according to expressed sequence tag (EST) databases. Gene expression profiles were obtained from five human retinas, two livers, and the cerebral cortical regions of two brains. Each sample was studied in duplicate, using a reference sample experimental design. Retina-enriched genes were identified by using the significance analysis for microarray (SAM) algorithm. Quantitative real time PCR was used to confirm microarray results. Bioinformatic analysis was performed to compare the array results with expression data available from public databases. Results The cDNA microarray contains 10,034 sequences: 67% represent known genes and 33% represent ESTs. Differential hybridization with the array identified, in addition to known retinal genes, 186 retina-enriched genes that do not have known retinal function. Of these, 96 represent novel genes. Quantitative real-time PCR of 11 of the identified genes and ESTs confirmed their retina-enriched expression pattern. Bioinformatic analysis of EST databases suggests that of the 186 genes, approximately 40% are predominantly expressed in the retina, whereas the remainder show significant expression in other tissues. Comparison of this study's microarray-based retina-enriched gene set with three published similar sets identified using complementary high-throughput approaches demonstrated only limited overlap of the identified genes. Conclusions Because previous studies have demonstrated that many retina-enriched genes are crucial for maintaining normal retinal function, the genes identified here are likely to include ones that have important roles in the retina and ones that when mutated can cause or modulate retinal disease. In addition, the retina custom array should provide a useful resource for comparing expression profiles between normal and diseased human retinas.
Published: 2003

45. Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat

Author: Arnold B. Rabson, Thomas M. Folks, Elia J. Duh, Wendy Maury, and Anthony S. Fauci
Subjects: Genes, Viral, viruses, Molecular Sequence Data, Regulatory Sequences, Nucleic Acid, Biology, Transfection, Virus, Cell Line, Chloramphenicol acetyltransferase, Transcription (biology), Humans, Transcription factor, Repetitive Sequences, Nucleic Acid, Multidisciplinary, Base Sequence, Tumor Necrosis Factor-alpha, Nuclear Proteins, Virology, Molecular biology, Long terminal repeat, DNA-Binding Proteins, Regulatory sequence, DNA, Viral, HIV-1, Virus Activation, HIV Long Terminal Repeat, Protein Binding, Research Article
Abstract: Expression of human immunodeficiency virus type 1 (HIV-1) can be activated in a chronically infected T-cell line (ACH2 cells) by a cytokine, human tumor necrosis factor alpha (TNF-alpha). TNF-alpha treatment of ACH2 cells resulted in an increase in steady-state levels of HIV RNA and HIV transcription. Gel mobility shift assays demonstrated that the transcriptional activation of the HIV long terminal repeat (LTR) by TNF-alpha was associated with the induction of a nuclear factor(s) binding to the NF-kappa B sites in the LTR. Deletion of the NF-kappa B sites from the LTR eliminated activation by TNF-alpha in T cells transfected with plasmids in which the HIV LTR directed the expression of the bacterial chloramphenicol acetyltransferase gene. Thus, TNF-alpha appears to activate HIV RNA and virus production by ACH2 cells through the induction of transcription-activating factors that bind to the NF-kappa B sequences in the HIV LTR.
Published: 1989

46. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone

Author: Elia J. Duh, Anthony S. Fauci, John H. Kehrl, Jesse S. Justement, Kathleen A. Clouse, Arnold B. Rabson, and Thomas M. Folks
Subjects: Genes, Viral, Cell Survival, medicine.medical_treatment, T-Lymphocytes, Clone (cell biology), Biology, Transfection, Virus, Cell Line, Cell surface receptor, medicine, Humans, Promoter Regions, Genetic, Multidisciplinary, Tumor Necrosis Factor-alpha, Virology, Recombinant Proteins, Clone Cells, Cytokine, Gene Expression Regulation, Cell culture, HIV-1, Tumor necrosis factor alpha, HIV Long Terminal Repeat, Research Article
Abstract: Tumor necrosis factor alpha (TNF-alpha), also known as cachectin, was demonstrated to induce the expression of human immunodeficiency virus (HIV) in a chronically infected T-cell clone (ACH-2). Concentrations of recombinant TNF-alpha as low as 50 pg/ml induced a significant increase over background of HIV expression in the ACH-2 cells as determined by supernatant reverse transcriptase activity. The HIV-inducing effects of TNF-alpha could not be explained by toxic effects on the cells. In addition, both the uninfected parental cell line (A3.01) and the infected ACH-2 cells were shown to have high-affinity receptors for TNF-alpha. Transient-transfection experiments demonstrated that the inductive effects of TNF-alpha were due to specific activation of the HIV long terminal repeat. These studies provide evidence that TNF-alpha may play a role in the mechanisms of pathogenesis of HIV infection.
Published: 1989

47. Activation of the human immunodeficiency virus long terminal repeat by herpes simplex virus type 1 is associated with induction of a nuclear factor that binds to the NF-kappa B/core enhancer sequence

Author: Arnold B. Rabson, E. E. Max, Howard E. Gendelman, Elia J. Duh, J. M. Gimble, and Jeffrey M. Ostrove
Subjects: Exonucleases, Simplexvirus, food.ingredient, Virus Cultivation, viruses, Immunology, Molecular Sequence Data, Biology, medicine.disease_cause, Transfection, Microbiology, food, Virology, Gene expression, medicine, Enhancer, Transcription factor, Repetitive Sequences, Nucleic Acid, Base Sequence, Molecular biology, Long terminal repeat, DNA-Binding Proteins, Herpes simplex virus, Enhancer Elements, Genetic, Insect Science, HIV-1, Electrophoresis, Polyacrylamide Gel, Virus Activation, HIV Long Terminal Repeat, Plasmids, Transcription Factors, Research Article
Abstract: It has been previously shown that herpes simplex virus type 1 (HSV-1) infection of HeLa cells results in augmentation of gene expression directed by the human immunodeficiency virus (HIV) long terminal repeat (LTR). This effect is presumably mediated by protein interactions with the LTR. We have used two different assays of DNA-protein interactions to study the HSV-induced activation of the HIV LTR. Activation of the HIV LTR is associated with increased protein binding to LTR sequences in a region including the NF-kappa B/core enhancer and the Sp1 binding sequences as monitored by an exonuclease protection assay. Gel retardation assays demonstrated that HSV-1 infection resulted in the induction of a nuclear factor(s) that binds to the NF-kappa B/core enhancer sequence. In addition to the activation of the HIV LTR, HSV induction of NF-kappa B activity may be important for the regulation of HSV gene expression during a herpesvirus infection.
Published: 1988

48. Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Author: Laura M. Thornton, Paul Lichtenstein, Verneri Anttila, Diego Albani, Josep Antoni Ramos-Quiroga, Roger A.H. Adan, Monika Schlögelhofer, Stephen Sanders, Enrique Castelao, Klaus Berger, Nina Dalkner, Urs Heilbronner, Engilbert Sigurdsson, Pablo Mir, Fuquan Zhang, James T.R. Walters, Patrick F. Sullivan, Fragiskos Gonidakis, F. Kyle Satterstrom, Sara Marsal, Per Hoffmann, Amy Perry, Valentina Ciullo, Beate Herpertz-Dahlmann, Catharina Lavebratt, Kieran C. Murphy, Tammy Hedderly, Hyun Ju Hong, Evald Saemundsen, Sascha B. Fischer, Hailiang Huang, Andrew D. Grotzinger, Nienke Vulink, Murray B. Stein, Mark A. Frye, Laura J. Scott, David Curtis, Todd Lencz, Janiece E. DeSocio, Richard A. Belliveau, Eduard Vieta, Andrea Dietrich, Wade H. Berrettini, Kenneth S. Kendler, Marquis P. Vawter, Paul S. Nestadt, Michael E. Talkowski, Manuel Mattheisen, Ingrid Agartz, Elisa Docampo, Bernhard T. Baune, Stefan Ehrlich, Jolanta Lissowska, Felecia Cerrato, Terje Nærland, Robin M. Murray, Jennifer Reichert, Annette M. Hartmann, Hannelore Ehrenreich, Howard J. Edenberg, Katherine A. Halmi, Qingqin S. Li, Peristera Paschou, Marie Bækvad-Hansen, Esther Walton, Alessio Maria Monteleone, Ted Reichborn-Kjennerud, Frank Bellivier, Jungeun Song, D. Blake Woodside, Young Shin Kim, Jochen Seitz, Jacques Pantel, Palmiero Monteleone, Erika L. Nurmi, Rodney J. Scott, Kang Sim, Ekaterina A. Khramtsova, Udo Dannlowski, Rolf Adolfsson, Danielle Posthuma, Melissa J. Green, Laura Ibanez-Gomez, Jakob Grove, Elvira Bramon, Gregory L. Hanna, Cynthia M. Bulik, Yiran Guo, Stephan Ripke, Mary M. Robertson, Harald N. Aschauer, Adebayo Anjorin, Joanna Martin, Bertram Müller-Myhsok, Deborah Kaminská, Jose Guzman-Parra, Benedetta Nacmias, Erik G. Jönsson, Jonathan R. I. Coleman, Douglas F. Levinson, Hamdi Mbarek, Gun Peggy Knudsen, Karin Egberts, Mette Nyegaard, Patrik K. E. Magnusson, Mark Adams, Douglas Blackwood, Elisabeth B. Binder, Marcus Ising, Anna R. Docherty, Jim van Os, Nese Direk, Lina Martinsson, Maria Arranz, Christel M. Middeldorp, Stefan Kloiber, Sintia Iole Belangero, Eske M. Derks, Ingrid Melle, Erlend Bøen, Jan Haavik, Federica Piras, Unna N. Danner, Anil K. Malhotra, Gerome Breen, Stephen V. Faraone, Amanda B Zheutlin, Timothy Poterba, Stephan Ruhrmann, Inge Joa, Ulrik Fredrik Malt, Sarah E. Bergen, Federica Tozzi, Lauren A. Weiss, Hana Papezova, Dominic Holland, Elliot S. Gershon, Jaakko Kaprio, Merete Nordentoft, Scott D. Gordon, Christopher Pittenger, Keun-Ah Cheon, Jennifer Jordan, Philip Gorwood, Myrna M. Weissman, Preben Bo Mortensen, Melissa A. Munn-Chernoff, Isobel Heyman, Eun-Young Shin, Christie L. Burton, Katherine Gordon-Smith, Sietske G. Helder, Peter Nagy, Till F. M. Andlauer, Yunpeng Wang, Young Key Kim, Kate Langley, Søren Dalsgaard, Richard Delorme, Torbjørn Elvsåshagen, Bennett L. Leventhal, Giovanni Gambaro, Christos Androutsos, Jennifer Tübing, Marion Roberts, Annelie Nordin Adolfsson, Hakon Hakonarson, Dorothy E. Grice, Vaughan J. Carr, Konstantinos Tziouvas, Stephanie Zerwas, Cathy L. Barr, Michael Conlon O'Donovan, Per Qvist, Beate St Pourcain, Samuel Kuperman, Leila Karhunen, Jack Samuels, Markus M. Nöthen, Martien J H Kas, Alfonso Tortorella, Mikael Landén, Jennifer Crosbie, Marco A. Grados, Joanna M. Biernacka, Paul D. Arnold, Irene A. Malaty, Jurjen J. Luykx, Nicholas Bass, Naomi R. Wray, Catharina A. Hartman, Christina M. Hultman, Michael S. Okun, Brandon Wormley, Michael Bauer, Daniel J. Smith, Ian Jones, Kathryn Roeder, Brien P. Riley, Caroline M. Nievergelt, Katrin Gade, Sarah Kittel-Schneider, Roy H. Perlis, James R. Mitchell, Ziarih Hawi, James Lee, Liz Forty, William E. Bunney, Thomas Damm Als, Catherine Schaefer, Digby Quested, Matteo Cassina, Anna C. Koller, Patrick Turley, Agnes A. Steixner, Anu Raevuori, Assen Jablensky, Peter Holmans, Dong-Ho Song, S. Evelyn Stewart, Jan K. Buitelaar, Fernando S. Goes, Alexander Münchau, Ayman H. Fanous, Nicolas Ramoz, James B. Potash, Monica Gratacos Mayora, Tobias Banaschewski, Céline S. Reinbold, Renata Rizzo, Arianna Di Florio, Lenka Foretova, Gianfranco Spalletta, Aarno Palotie, Eleftheria Zeggini, Lawrence W. Brown, Julie K. O'Toole, Lynn E. DeLisi, Ulrich Schall, Mary Roberson, Barbara J. Coffey, Bryan J. Mowry, Murray J. Cairns, Dan J. Stein, Glyn Lewis, Marta Ribasés, C. Robert Cloninger, Bettina Konte, John B. Vincent, Duncan S. Palmer, Radhika Kandaswamy, Christine Ladd-Acosta, Lars Alfredsson, Frank Visscher, Ulrike Schmidt, Aiden Corvin, Susan L. Santangelo, Brenda W.J.H. Penninx, David J. Porteous, Tetsuya Ando, Arne E. Vaaler, Bru Cormand, Laura Carlberg, Claire Churchhouse, Manfred Stuhrmann, Niamh Mullins, Christine Søholm Hansen, Cathy L. Budman, Hartmut Imgart, Dan E. Arking, James J. McGough, Michael Gill, Christel Depienne, Roland Burghardt, Antonio Julià, Anders M. Dale, Sven Sandin, Katharina Domschke, Maria Grigoroiu-Serbanescu, Susana Jiménez-Murcia, Marianne Giørtz Pedersen, Zsanett Tarnok, Gisli Baldursson, Michele T. Pato, David M. Hougaard, Thorgeir E. Thorgeirsson, Katharina Bey, Kerstin J. Plessen, Margaret A. Richter, Ole A. Andreassen, Claudine Laurent-Levinson, Leonid Padyukov, Jacques Mallet, Daniela Degortes, John R. Kelsoe, Robert D. Levitan, Andreas Reif, Chaim Huyser, Derek W. Morris, Sina Wanderer, William Byerley, Edna Grünblatt, E.J.C. de Geus, Hyejung Won, Josephine Elia, Rudolf Uher, Jay A. Tischfield, Andreas Karwautz, Gustavo Turecki, Pieter J. Hoekstra, Dorret I. Boomsma, Jacob Rosenthal, Daniele Cusi, Michael C. Neale, Sara Mostafavi, Gwyneth Zai, F. Anthony O'Neill, Gary Donohoe, Karola Rehnström, Harry Brandt, Helena Gaspar, Francis J. McMahon, H-Erich Wichmann, Andrew W. Bergen, Giovanni Coppola, Lea K. Davis, Lenka Slachtova, Olav B. Smeland, Erin C. Dunn, Nicholas G. Martin, Allan L. Naarden, Jo Knight, Cristina Sánchez-Mora, Masashi Ikeda, Lorraine Southam, Sandro Sorbi, Barbara Franke, Martin Schalling, Russell Schachar, Yen-Chen Anne Feng, Kirsten R. Müller-Vahl, André Scherag, Zhaozhong Zhu, Eric A. Storch, Páll Magnússon, David Cohen, Olafur O Gudmundsson, Harvey S. Singer, Brian Kelly, Jonas Bybjerg-Grauholm, Blanca Garcia-Delgar, Thomas Hansen, Carmel M. Loughland, Christine Lochner, Stacy Steinberg, Martin Woods, Jorge A. Quiroz, Raquel Rabionet, Alden Y. Huang, Janice M. Fullerton, María Soler Artigas, Hans J. Grabe, Philip Asherson, Margit Burmeister, Alicia R. Martin, Martin A. Kennedy, Janet Treasure, Anders D. Børglum, Eva C. Schulte, Andreas Hartmann, Frans Henskens, Youl-Ri Kim, Jens Treutlein, Joanna Hauser, Manfred M. Fichter, Damiaan Denys, Ann E. Pulver, Kelly L. Klump, Paul Sandor, Michael Wagner, Philippe Courtet, Sandra Van der Auwera, Susanne Lucae, Eystein Stordal, Michel G. Nivard, Maurizio Clementi, Astrid Morer, Philip B. Mitchell, Huda Akil, Edwin H. Cook, Jennifer L. Moran, Donald W. Black, Jeremiah M. Scharf, Jana Strohmaier, Colm McDonald, Meg M.-J. Wang, Richard M. Myers, Stephanie Godard, Pablo V. Gejman, Athanasios Maras, Marcella Rietschel, Nancy G. Buccola, Konstantinos Hatzikotoulas, Dalila Pinto, Jouke-Jan Hottenga, Kari Stefansson, James S. Sutcliffe, Andres Metspalu, Amaia Hervás, Joel Gelernter, Wolfgang Herzog, Paula Rovira, Gunnar Morken, Tara Murphy, Mark Weiser, Vincent Millischer, Frank Dudbridge, Dan Rujescu, Vladimir Bencko, Valdo Ricca, Kimberly Chambert, Guy A. Rouleau, James J. Crowley, Thomas G. Schulze, Toni-Kim Clarke, Triinu Peters, Gudrun Wagner, Daniel A. Geller, Henry R. Kranzler, G. Bragi Walters, Vera Golimbet, Clement C. Zai, Nigel Williams, Andreas Birgegård, Joseph D. Buxbaum, Elliot M. Tucker-Drob, Jerome C. Foo, Tracey L. Petryshen, Daniel P. Howrigan, Hunna J. Watson, Franziska Degenhardt, Peter R. Schofield, Jesper Buchhave Poulsen, Stefan Herms, Johannes Hebebrand, Mario Maj, George Kirov, Fabrizio Piras, Sara McDevitt, James T. McCracken, Carol A. Mathews, Michael John Owen, Peter Falkai, Donald L. Gilbert, Enda M. Byrne, Fernando Fernández-Aranda, Csaba Barta, Stéphane Jamain, Jubao Duan, Dongmei Yu, Danielle C. Cath, Ole Mors, Sigrun Hope, Laramie E. Duncan, Alan R. Sanders, Sang-Yun Oh, Carsten Bøcker Pedersen, Henning Tiemeier, Roseann E. Peterson, Raymond K. Walters, Margarita C T Slof-Op 't Landt, Madeline Alexander, Stephanie Le Hellard, Ina Giegling, Annemarie A. van Elburg, Steven P. Hamilton, Vesna Boraska Perica, Thomas V. Fernandez, Danielle M. Dick, Francesco Bettella, Roel A. Ophoff, Grant W. Montgomery, Gerald Nestadt, Nakao Iwata, Jessica H. Baker, Walter H. Kaye, Jeremy M. Silverman, Mark J. Daly, Robert A. King, Sarah E. 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Subjects: Netherlands Twin Register (NTR), cross-disorder genetics, Medizin, Genome-wide association study, Tourette syndrome, functional genomics, gene expression, genetic architecture, genetic correlation, GWAS, neurodevelopment, pleiotropy, psychiatric disorders, Psychiatric genetics, 0302 clinical medicine, Pleiotropy, functional genomic, WIDE ASSOCIATION, cross-disorder genetic, 0303 health sciences, Mental Disorders, Genetic Pleiotropy, HUMAN BRAIN, INSIGHTS, Autism spectrum disorder, Schizophrenia, DISEASES, GENETIC CORRELATIONS, medicine.medical_specialty, Neurogenesis, Quantitative Trait Loci, BF, Biology, GENOTYPE IMPUTATION, Psychiatric geneticscross-disorder geneticspsychiatric disorderspleiotropyneurodevelopmentGWASgenetic correlationgene expressiongenetic architecturefunctional genomics, Article, General Biochemistry, Genetics and Molecular Biology, psychiatric disorder, 03 medical and health sciences, SDG 3 - Good Health and Well-being, medicine, Humans, Genetic Predisposition to Disease, Bipolar disorder, TRANSCRIPTOME, Psychiatry, 030304 developmental biology, Gwas, Psychiatric Genetics, Cross-disorder Genetics, Functional Genomics, Gene Expression, Genetic Architecture, Genetic Correlation, Neurodevelopment, Psychiatric Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, MUTATIONS, medicine.disease, Genetic architecture, DEMETHYLASE, RC0321, 1182 Biochemistry, cell and molecular biology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.
Published: 2019

49. Psychiatric genome-wide association study analyses implicate neuronal, immune and histone pathways

Author: Anita Thapar, Lena Backlund, Lindsey Kent, Walter J. Muir, A. Jeremy Willsey, Sandra K. Loo, Michael Boehnke, Christa Lese Martin, Ania Korszun, Guiomar Oliveira, Veronica J. Vieland, Stephen W. Scherer, René S. Kahn, Darina Czamara, Jeremy R. Parr, Michael E. Goddard, Willem A. Nolen, Josep Antoni Ramos-Quiroga, Stephen Sanders, Karola Rehnstroem, Nelson B. Freimer, Erin N. Smith, Ann Olincy, Ingrid Melle, Myrna M. Weissman, James A. Knowles, William Byerley, Aravinda Chakravarti, Shaun Purcell, Jens Treutlein, Sebastian Zoellner, Hakon Hakonarson, Susanne Lucae, Markus M. Noethen, Ian B. Hickie, Marion Friedl, Srinivasa Thirumalai, Stephen Newhouse, Joseph Piven, Andrew M. McIntosh, Cathryn M. Lewis, Srdjan Djurovic, Francis J. McMahon, Ayman H. Fanous, Bernie Devlin, Steven A. McCarroll, Alan F. Schatzberg, Peter Szatmari, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Gerard van Grootheest, Phil Lee, Richard Anney, Elaine K. Green, Geraldine Dawson, Joseph A. Sergeant, Digby Quested, Magdalena Gross, Jack D. Barchas, Nicholas G. Martin, Timothy W. Yu, Jouke-Jan Hottenga, Mark Lathrop, Federica Tozzi, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Sandra Meier, Louise Gailagher, David A. Collier, Farooq Amin, Michael C. Neale, Martin Schalling, Lieuwe de Haan, Bru Cormand, Falk W. Lohoff, Jennifer Crosbie, Howard J. Edenberg, Aarno Palotie, Johannes H. Smit, Robert Freedman, Katherine Gordon-Smith, Michele L. Pergadia, Enda M. Byrne, Hans-Christoph Steinhausen, Benjamin M. Neale, Anjali K. Henders, Michele T. Pato, Manuel Mattheisen, Urban Ösby, Edward M. Scolnick, Evaristus A. Nwulia, Fritz Poustka, Gonneke Willemsen, Andrew C. Heath, David St. Cair, Emma M. Quinn, I. Nicol Ferrier, John R. Kelsoe, Vanessa Hus, Andrew McQuillin, John P. Rice, William M. McMahon, Joseph Biederman, Danyu Lin, Wolfgang Maier, Frans G. Zitman, Josephine Elia, Nicholas J. Schork, Stéphane Jamain, Lizzy Rossin, Jubao Duan, Ingrid Agartz, Devin Absher, Jordan W. Smoller, Matthew W. State, Richard M. Myers, Shrikant Mane, Carlos N. Pato, William E. Bunney, Marian L. Hamshere, Manfred Uhr, Nicholas John Craddock, Astrid M. Vicente, Tobias Banaschewski, David Curtis, Anne Farmer, Scott D. Gordon, Anna K. Kaehler, Eric M. Morrow, Marcella Rietschel, Patrik K. E. Magnusson, Klaus-Peter Lesch, Rebecca McKinney, Jana Strohmaier, Thomas F. Wienker, Pablo V. Gejman, Douglas Blackwood, Maria Helena Pinto de Azevedo, Tiffany A. Greenwood, Don H. Linszen, Daniel L. Koller, Richard Bruggeman, Vinay Puri, Naomi R. Wray, Stanley J. Watson, Elena Maestrini, Valentina Moskvina, Frank Dudbridge, Danielle Posthuma, Edward G. Jones, Lambertus Klei, Sarah E. Bergen, Fan Meng, Steven P. Hamilton, Guy A. Rouleau, Pierandrea Muglia, Mikael Landén, Stephanie H. Witt, Laramie E. Duncan, Stanley Zammit, Judith A. Badner, Florian Holsboer, Eco J. C. de Geus, Daniel Moreno-De-Luca, Benjamin S. Pickard, Gunnar Morken, Michael Conlon O'Donovan, Michael Steffens, Kathryn Roeder, Dorret I. Boomsma, Paul D. Shilling, Stephan Ripke, Nigel Williams, Jeremy M. Silverman, David Craig, Mark J. Daly, Michael Bauer, Detelina Grozeva, Markus J. Schwarz, Peter Holmans, Hugh Gurling, T. Scott Stroup, Aribert Rothenberger, Gary Donohoe, Eric Fombonne, Joseph D. Buxbaum, Matthew Flicldnger, Bryan J. Mowry, Thomas Hansen, Ina Giegling, Grant W. Montgomery, Caroline M. Nievergelt, Susan L. Smalley, Jung-Ying Tzeng, David H. Ledbetter, Christopher A. Walsh, Gerard D. Schellenberg, Sarah E. Medland, Robert D. Oades, James B. Potash, Dan E. Arking, Johannes Schumacher, Michael Gill, James J. McGough, Jennifer L. Moran, Donald W. Black, Sian Caesar, Neelroop N. Parikshak, Ian W. Craig, Sabine M. Klauck, Wade H. Berrettini, T. Foroud, Peter P. Zandi, Inez Myin-Germeys, Marcus Ising, Sven Cichon, Alexandre A. Todorov, Mònica Bayés, Thomas Werge, Susan L. Slager, Stanley I. Shyn, Jim van Os, Derek W. Morris, Douglas M. Ruderfer, Thomas W. Muehleisen, Matthew C. Keller, Susmita Datta, Ian Jones, John B. Vincent, James L. Kennedy, Anthony P. Monaco, Jianxin Shi, Dale R. Nyholt, Bruno Etain, Christine Fraser, Paul Cormican, Miguel Casas, Radhika Kandaswamy, Gerome Breen, Stephen V. Faraone, Jonna Kuntsi, Thomas Bettecken, Witte J.G. Hoogendijk, Nancy G. Buccola, Franziska Degenhardt, Lyudmila Georgieva, Marion Leboyer, Alan R. Sanders, John Strauss, Dan Rujescu, Russell Schachar, Helena Medeiros, Lisa Jones, Peter M. Visscher, Lauren A. Weiss, René Breuer, John I. Nurnberger, Andreas Reif, Phoenix Kwan, Vihra Milanova, Chunyu Liu, Martin A. Kohli, Donald J. MacIntyre, Nicholas Bass, Khalid Choudhury, Edwin H. Cook, Catherine Lord, Andrew D. Paterson, Jobst Meyer, Richard P. Ebstein, Zhaoming Zhao, Niklas Laengstroem, Thomas G. Schulze, Peter Propping, Wei Xu, Robert C. Thompson, Kimberly Chambert, Jonathan Pimm, Ivan Nikolov, Pamela A. F. Madden, Kevin A. McGhee, Jacob Lawrence, Jan K. Buitelaar, Andres Ingason, Christine M. Freitag, Robert Krasucki, Wiepke Cahn, Rita M. Cantor, Christina M. Hultman, Melvin G. McInnis, Catalina Betancur, Eftichia Duketis, Michael T. Murtha, Thomas H. Wassink, Philip Asherson, John S. Witte, Elaine Kenny, Edmund J.S. Sonuga-Barke, Lydia Krabbendam, Line Olsen, Agatino Battaglia, Laura J. Scott, Annette M. Hartmann, Yunjung Kim, Richard O. Day, Edwin J. C. G. van den Oord, Ole A. Andreassen, Herbert Roeyers, Michael John Owen, Colm O'Dushlaine, Peng Zhang, Morten Mattingsdal, Michael L. Cuccaro, Margaret A. Pericak-Vance, Joachim Hallmayer, Jun Li, Pamela B. Mahon, Elisabeth B. Binder, William A. Scheftner, Daniel H. Geschwind, Christel M. Middeldorp, Josef Frank, Keith Matthews, Jennifer K. Lowe, Paul Lichtenstein, Verneri Anttila, Pamela Sklar, Szabocls Szelinger, Roel A. Ophoff, Peter McGuffin, Stefan Herms, Bettina Konte, George Kirov, Hilary Coon, Maria Hipolito, Louise Frisén, Kenneth S. Kendler, Frank Bellivier, James S. Sutdiffe, Jeffrey A. Lieberman, Todd Lencz, Susanne Hoefels, Alan W. McLean, Barbara Franke, Huda Akil, Soumya Raychaudhuri, Ellen M. Wijsman, Vishwajit L. Nimgaonkar, Roy H. Perlis, Patrick J. McGrath, Susan L. Santangelo, William Coryell, Henrik B. Rasmussen, Weihua Guan, William Lawson, Elliot S. Gershon, Sean Ennis, Aiden Corvin, Allan H. Young, Thomas B. Barrett, Jonathan L. Haines, Douglas F. Levinson, Ana Miranda, Anil K. Malhotra, S. Hong Lee, Stan F. Nelson, Anthony J. Bailey, Patrick F. Sullivan, Dorothy E. Grice, Lefkos T. Middleton, Bertram Mueller-Myhsok, Michael R. 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Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Human genetics, Psychiatry, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Gastroenterology & Hepatology, Hematology, University of St Andrews. School of Medicine, University of St Andrews. Institute of Behavioural and Neural Sciences, Psychiatrie & Neuropsychologie, MUMC+: MA Psychiatrie (3), MUMC+: Hersen en Zenuw Centrum (3), RS: MHeNs - R2 - Mental Health, ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Universitat de Barcelona, Perceptual and Cognitive Neuroscience (PCN), Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Complex Trait Genetics, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, LEARN! - Brain, learning and development, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, EMGO+ - Mental Health, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), O'Dushlaine, Colm, Rossin, Lizzy, Lee, Phil H, Duncan, Laramie, Lee, S Hong, Breen, Gerome, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, and Myin-Germeys, Inez
Subjects: Netherlands Twin Register (NTR), Statistical methods, Autism, Medizin, LOCI, Genome-wide association study, heritability, Genome-wide association studies, Histones, Genètica mèdica, 0302 clinical medicine, Histone methylation, Databases, Genetic, 2.1 Biological and endogenous factors, Psychology, GWAS, Aetiology, Psychiatric genetics, R2C, bipolar disorder, Psychiatry, 0303 health sciences, Disorders, Loci, Depression, General Neuroscience, Mental Disorders, Medical genetics, METHYLATION, Brain, 3rd-DAS, Serious Mental Illness, Psychiatric Disorders, 3. Good health, Histone, Mental Health, Schizophrenia, Mental Disorder, Cognitive Sciences, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Promoters, BDC, BURDEN, RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry, Human, Signal Transduction, medicine.medical_specialty, DISORDERS, Genomics, Network and Pathway Analysis Subgroup of Psychiatric Genomics Consortium, Burden, Biology, Methylation, Article, Biological pathway, PROMOTERS, 03 medical and health sciences, Databases, Genetic, medicine, Genetics, Humans, Genetic Predisposition to Disease, histone methylation, Bipolar disorder, Psiquiatria, AUTISM, 030304 developmental biology, Genetic association, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Human Genome, Neurosciences, medicine.disease, Brain Disorders, Good Health and Well Being, DE-NOVO MUTATIONS, Perturbações do Desenvolvimento Infantil e Saúde Mental, RC0321, Genome-wide Association Studies, De-novo mutations, major depression, Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: G.B. and S.N. acknowledge funding support for this work from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. P.H.L. is supported by US National Institute of Mental Health (NIMH) grant K99MH101367. Genome-wide association studies (GWAS) of psychiatric disorders have identified multiple genetic associations with such disorders, but better methods are needed to derive the underlying biological mechanisms that these signals indicate. We sought to identify biological pathways in GWAS data from over 60,000 participants from the Psychiatric Genomics Consortium. We developed an analysis framework to rank pathways that requires only summary statistics. We combined this score across disorders to find common pathways across three adult psychiatric disorders: schizophrenia, major depression and bipolar disorder. Histone methylation processes showed the strongest association, and we also found statistically significant evidence for associations with multiple immune and neuronal signaling pathways and with the postsynaptic density. Our study indicates that risk variants for psychiatric disorders aggregate in particular biological pathways and that these pathways are frequently shared between disorders. Our results confirm known mechanisms and suggest several novel insights into the etiology of psychiatric disorders. Postprint
Published: 2015

50. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs

Author: Laura J. Scott, Bernie Devlin, Steven A. McCarroll, James S. Sutcliffe, Stefan Herms, Yunjung Kim, Richard O. Day, Thomas F. Wienker, Frank Dudbridge, I. Nicol Ferrier, Bettina Konte, Marta Ribasés, C. Robert Cloninger, Brenda W.J.H. Penninx, Detelina Grozeva, Herbert Roeyers, Peter Holmans, Colm O'Dushlaine, Scott D. Gordon, Sarah E. Bergen, Fan Meng, Morten Mattingsdal, Hugh Gurling, Ina Giegling, Gerard van Grootheest, Ania Korszun, Markus J. Schwarz, George Kirov, Sebastian Zöllner, Kenneth S. Kendler, Nicholas G. Martin, Michael Conlon O'Donovan, Michael C. Neale, Jim van Os, Aravinda Chakravarti, Timothy W. Yu, Mikael Landén, Inez Myin-Germeys, Markus M. Nöthen, Kathryn Roeder, James B. Potash, Alan W. McLean, Louise Gallagher, Anna K. Kähler, Thomas Bettecken, Nigel Williams, Frank Bellivier, Joseph D. Buxbaum, Derek W. Morris, Susan L. Smalley, Jung-Ying Tzeng, Martin Schalling, Douglas M. Ruderfer, Caroline M. Nievergelt, T. Scott Stroup, David H. Ledbetter, Jennifer Crosbie, Anita Thapar, Barbara Franke, Jeffrey A. Lieberman, Huda Akil, Miguel Casas, Daniel H. Geschwind, Paul Cormican, Bertram Müller-Myhsok, Lyudmila Georgieva, Robert Krasucki, Martin Hautzinger, Alysa E. Doyle, Cinnamon S. Bloss, Gerard D. Schellenberg, Todd Lencz, Melvin G. McInnis, Catalina Betancur, Josep Antoni Ramos-Quiroga, Stephen Sanders, Eftichia Duketis, Don H. Linszen, Matthew W. State, Richard M. Myers, Soumya Raychaudhuri, Lizzy Rossin, Howard J. Edenberg, Michael E. Goddard, S. Hong Lee, Elisabeth B. Binder, Pablo V. Gejman, William A. Scheftner, Wolfgang Maier, Judith A. Badner, Christel M. Middeldorp, Maria Helena Pinto de Azevedo, Johannes H. Smit, Willem A. Nolen, Lieuwe de Haan, Gonneke Willemsen, Keith Matthews, Ellen M. Wijsman, Jennifer K. Lowe, Rebecca McKinney, Magdalena Gross, Dorothy E. Grice, James A. Knowles, Andrew C. Heath, Jana Strohmaier, Vishwajit L. Nimgaonkar, William Byerley, William E. Bunney, Dan E. Arking, Andrew McQuillin, William M. McMahon, Manuel Mattheisen, Hans-Christoph Steinhausen, Joseph Biederman, Guy A. Rouleau, James J. McGough, Sian Caesar, Edward M. Scolnick, Lefkos T. Middleton, Jack D. Barchas, Ian B. Hickie, Danyu Lin, Patrik K. E. Magnusson, Douglas Blackwood, Francis J. McMahon, Ingrid Agartz, Elena Maestrini, Marian L. Hamshere, Lindsey Kent, Walter J. Muir, Stephan Ripke, Lydia Krabbendam, Christine Fraser, Maria Hipolito, Louise Frisén, Eric Fombonne, Emma M. Quinn, Michael Bauer, Richard P. Ebstein, Michael Steffens, Jordan W. Smoller, Stanley J. Watson, Michael Boehnke, Philip Asherson, Agatino Battaglia, Elliot S. Gershon, Russell Schachar, Marcus Ising, Peng Zhang, Margaret A. Pericak-Vance, Joachim Hallmayer, Sean Ennis, Radhika Kandaswamy, René S. Kahn, Susanne Hoefels, Thomas W. Mühleisen, Pamela Sklar, Paul Lichtenstein, Verneri Anttila, Michael L. Cuccaro, Florian Holsboer, René Breuer, Eric M. Morrow, Vinay Puri, Naomi R. Wray, Szabocls Szelinger, Sabine M. Klauck, John B. Vincent, Shrikant Mane, Aribert Rothenberger, Marion Friedl, Ian Jones, Khalid Choudhury, Michael R. Barnes, Adebayo Anjorin, Edwin H. Cook, William Lawson, Allan H. Young, Lambertus Klei, Bryan J. Mowry, Johannes Schumacher, Michael Gill, James L. Kennedy, Marcella Rietschel, Aiden Corvin, Henrik B. Rasmussen, Susmita Datta, Kimberly Chambert, Daniel Moreno-De-Luca, Benjamin S. Pickard, Stan F. Nelson, Veronica J. Vieland, Stephen W. Scherer, Peter M. Visscher, John Strauss, Andreas Reif, Andrew D. Paterson, Ann Olincy, Phoenix Kwan, Anthony J. Bailey, Patrick F. Sullivan, Pierandrea Muglia, Gunnar Morken, Susanne Lucae, Ayman H. Fanous, Jacob Lawrence, Donald J. MacIntyre, Nancy G. Buccola, Rita M. Cantor, Christina M. Hultman, Weihua Guan, Anthony P. Monaco, Jouke-Jan Hottenga, Elaine Kenny, Jianxin Shi, Dale R. Nyholt, Kevin A. McGhee, Falk W. Lohoff, Jonna Kuntsi, Niklas Långström, John I. Nurnberger, Nelson B. Freimer, Erin N. Smith, John P. Rice, Michael T. Murtha, Thomas H. Wassink, Alexandre A. Todorov, Edmund J.S. Sonuga-Barke, Dan Rujescu, Roy H. Perlis, John S. Witte, Christopher A. Walsh, Matthew C. Keller, Pamela B. Mahon, Patrick J. McGrath, Susan L. Santangelo, Annette M. Hartmann, Ole A. Andreassen, Tatiana Foroud, Shaun Purcell, Josef Frank, Douglas F. Levinson, William Coryell, Ana Miranda, Alan F. Schatzberg, Peter Szatmari, Jun Li, Gerome Breen, Stephen V. Faraone, Anil K. Malhotra, Helena Medeiros, Martin A. Kohli, Nicholas Bass, Catherine Lord, Peter Propping, Wei Xu, Federica Tozzi, Ivan Nikolov, Jan K. Buitelaar, Thomas G. Schulze, Katherine Gordon-Smith, Michele L. Pergadia, Fritz Poustka, Valentina Moskvina, David Curtis, Tobias Banaschewski, Devin Absher, Danielle Posthuma, Stanley Zammit, Gary Donohoe, Ingrid Melle, Karola Rehnström, Thomas Hansen, Myrna M. Weissman, Stanley I. Shyn, Hakon Hakonarson, Christa Lese Martin, Digby Quested, Darina Czamara, Jeremy R. Parr, Pamela A. F. Madden, Jens Treutlein, Aarno Palotie, Robert Freedman, Sandra Meier, Bru Cormand, Nicholas J. Schork, Michele T. Pato, John R. Kelsoe, Vanessa Hus, Frans G. Zitman, Josephine Elia, David St Clair, Roel A. Ophoff, Peter McGuffin, Jonathan Pimm, Jonathan L. Haines, Wiepke Cahn, Matthew Flickinger, Steven P. Hamilton, Michael John Owen, Paul D. Shilling, Jeremy M. Silverman, David Craig, Mark J. Daly, Sarah E. Medland, Robert D. Oades, Marion Leboyer, Alan R. Sanders, Vihra Milanova, Chunyu Liu, Jobst Meyer, Dorret I. Boomsma, Evaristus A. Nwulia, Thomas B. Barrett, Jennifer L. Moran, Donald W. Black, Mònica Bayés, Witte J.G. Hoogendijk, Franziska Degenhardt, Benjamin M. Neale, Daniel L. Koller, Carlos N. Pato, Nicholas John Craddock, Richard Bruggeman, Enda M. Byrne, Edward G. Jones, Eco J. C. de Geus, Stéphane Jamain, Jubao Duan, Anne Farmer, Astrid M. Vicente, Grant W. Montgomery, Thomas Werge, Cathryn M. Lewis, Srdjan Djurovic, Phil Lee, Richard Anney, Elaine K. Green, Wade H. Berrettini, Peter P. Zandi, Susan L. Slager, Stephanie H. Witt, Ian W. Craig, Lisa Jones, Sven Cichon, Bruno Etain, Mark Lathrop, Hilary Coon, Robert C. Thompson, Lena Backlund, A. Jeremy Willsey, Andres Ingason, Christine M. Freitag, Sandra K. Loo, Guiomar Oliveira, Line Olsen, Edwin J. C. G. van den Oord, Geraldine Dawson, Joseph A. Sergeant, David A. Collier, Farooq Amin, Srinivasa Thirumalai, Manfred Uhr, Joseph Piven, Andrew M. McIntosh, Anjali K. Henders, Urban Ösby, Klaus-Peter Lesch, Tiffany A. Greenwood, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Perceptual and Cognitive Neuroscience (PCN), Lee, S Hong, Ripke, Stephan, Neale, Benjamin M, Faraone, Stephen V, Wray, Naomi R, Cross-Disorder Group of the Psychiatric Genomics Consortium, International Inflammatory Bowel Disease Genetics Consortium (IIBDGC), Queensland Brain Institute, University of Queensland [Brisbane], Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], SUNY Upstate Medical University, State University of New York (SUNY), Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Psychiatric and Neurodevelopmental Genetics Unit, Queensland Centre for Mental Health Research, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council (MRC)-School of Medicine [Cardiff], Cardiff University-Institute of Medical Genetics [Cardiff]-Cardiff University-Institute of Medical Genetics [Cardiff], New South Wales Department of Primary Industries (NSW DPI), Faculty of Land and Food Resources, University of Melbourne, HudsonAlpha Institute for Biotechnology [Huntsville, AL], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Diakonhjemmet Hospital, University of Michigan [Ann Arbor], University of Michigan System, Molecular and Behavioral Neuroscience Institute (MBNI), University of Michigan System-University of Michigan System, Emory University [Atlanta, GA], Oslo University Hospital [Oslo], University College of London [London] (UCL), Trinity College Dublin, Johns Hopkins University School of Medicine [Baltimore], MRC Social Genetic Developmental and Psychiatry Centre, Institute of Psychiatry, King's College London, University of Coimbra [Portugal] (UC), Karolinska Institutet [Stockholm], University of Chicago, University of British Columbia (UBC), Department of Child and Adolescent Psychiatry and Psychotherapy [Mannheim], Universität Heidelberg [Heidelberg] = Heidelberg University, Weill Medical College of Cornell University [New York], GlaxoSmithKline, Glaxo Smith Kline, Portland Veterans Administration Medical Center, Windeyer Institute for Medical Sciences, IRCCS Fondazione Stella Maris [Pisa], University Hospital Carl Gustav Carus [Dresden, Germany], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Centro Nacional de Analisis Genomico [Barcelona] (CNAG), Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), European Network of Bipolar Research Expert Centres (ENBREC), ENBREC, Department of Psychiatry [Philadelphia], University of Pennsylvania, Physiopathologie des Maladies du Système Nerveux Central, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche Phytopharmacie et Médiateurs Chimiques (UPMC), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Massachusetts General Hospital [Boston, MA, USA], University of Iowa [Iowa City], University of Edinburgh, Royal Hospital for Sick Children [Edinburgh], The Scripps Research Institute [La Jolla, San Diego], MRC Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London-The Institute of Psychiatry, Institute of Medical Sciences, University of Aberdeen, Social, Genetic and Developmental Psychiatry Centre (SGDP), King‘s College London, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, Department of Psychiatry, University of Groningen [Groningen]-University Medical Center Groningen [Groningen] (UMCG), Trinity College Dublin-St. James's Hospital, School of Nursing, Louisiana State University (LSU), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Department of Psychiatry and Human Behavior, University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Friedman Brain Institute, Mount Sinai, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Seaver Autism Center for Research and Treatment, Department of Neuroscience, Departments of Psychiatry, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Seaver Autism Center-, The Mindich Child Health & Development Institute, Friedman Brain Institute, The Mindich Child Health and Development Institute, University of California [San Francisco] (UC San Francisco), Department of Psychiatry, School of Clinical and Experimental Medicine, University of Alabama at Birmingham [ Birmingham] (UAB), Department of Human Genetics, Los Angeles, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Stanley Center for Psychiatric Research, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Mental Health Sciences Unit, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Academic Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Department of Disability and Human Development, University of Illinois [Chicago] (UIC), University of Illinois System-University of Illinois System, Department of Developmental Neuroscience, Neuropsychiatric Genetics Research Group, University of California [San Diego] (UC San Diego), John P. Hussman Institute for Human Genomics, University of Miami [Coral Gables], East London NHS Foundation Trust, Queen Mary University of London (QMUL), Max-Planck-Institut für Psychiatrie, Genetics Institute, Autism Speaks and the Department of Psychiatry, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), School of Neurology, Neurobiology and Psychiatry, Royal Victoria Infirmary, Medstar Research Institute, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry and Behavioral Sciences, University of Chicago-NorthShore University Health System, Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine (LSHTM), Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Goethe-Universität Frankfurt am Main, Psychology Department, National University of Singapore (NUS), Department of Biochemistry and Molecular Biology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indiana University System-Indiana University System, Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Service de psychiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University (VCU), University of Dundee School of Medicine, University of Dundee, Department of Biostatistics and Center for Statistical Genetics, University of Michigan System-University of Michigan System-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU), Department of Child Psychiatry, McGill University = Université McGill [Montréal, Canada]-Montreal Children's Hospital, McGill University Health Center [Montreal] (MUHC)-McGill University Health Center [Montreal] (MUHC), Howard University College of Medicine, University of Colorado [Denver], Center for Neurobehavioral Genetics, Department of Genomics, Department of Molecular Medicine, Department of Neurology, University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Medical Research Council-Cardiff University, Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Fisico-Quimica Biologica, Universidade Federal do Rio de Janeiro (UFRJ), Vanderbilt Brain Institute, Vanderbilt University School of Medicine [Nashville], Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania-University of Pennsylvania-Children’s Hospital of Philadelphia (CHOP ), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Institute for Human Genetics, Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Center for Genomic Medicine, Copenhagen University Hospital-Rigshospitalet [Copenhagen], Copenhagen University Hospital, Department of Clinical and Developmental Psychology, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Clinical Research Unit, Brain & Mind Research Institute-The University of Sydney, Functional Genomics, Neuronal Plasticity / Mouse Behaviour, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Medical Epidemiology and Biostatistics (MEB), Autism and Communicative Disorders Centre, Center for Human Genetic Research, Center for neuroscience-University of California [Davis] (UC Davis), Bioinformatics Research Center, North Carolina State University [Raleigh] (NC State), Norwegian University of Science and Technology [Trondheim] (NTNU), Norwegian University of Science and Technology (NTNU)-Norwegian University of Science and Technology (NTNU), Emory University [Atlanta, GA]-Atlanta Veterans Affairs Medical Center, Psychiatric Neurogenetics Section, Centre for Addiction and Mental Health, School of Medicine, University of St Andrews [Scotland], Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Division of Molecular Genome Analysis, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Ecology and Evolutionary Biology, Insitute of Neuroscience and Physiology, University of Gothenburg (GU), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Developmental Brain and Behaviour Unit, University of Southampton, Division of Psychiatric Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Statistical Genetics Group, Department of Human Genetics, Department of Pharmacy and Biotechnology, Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), Department of Psychiatry and Psychotherapy, Department of Mental Health, Johns Hopkins University and Hospital, W.M. Keck Biotechnology Resource Laboratory, Yale University [New Haven], Institutes of Neuroscience and Health and Society, Newcastle University [Newcastle], Genetic Epidemiology Unit, Queensland Institute of Medical Research, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Sorlandet Hospital HF, Division of Psychiatry, University of Edinburgh-Royal Edinburgh Hospital, Medical Genetics Section, University of Edinburgh-Western General Hospital, Unit on the Genetic Basis of Mood and Anxiety Disorders, National Institutes of Health [Bethesda] (NIH), Unidade de Neurodesenvolvimento e Autismo (UNDA), Hospital Pediatrico de Coimbra, Division of Mental Health and Addiction, Molecular Psychiatry Laboratory, University of Michigan System-University of Michigan System-Molecular and Behavioral Neuroscience Institute, Research and Development, First Psychiatric Clinic-Alexander University Hospital, Registo Oncológico Regional-Sul, Instituto Português de Oncologia de Francisco Gentil, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, St. Olav's Hospital, Brown University, Department of Molecular Biology, Cell Biology and Biochemistry, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Human Genetics Department, University of Pittsburgh (PITT), Institute for Biomedical Imaging and Life Science, University Medical Center [Utrecht]-Brain Center Rudolf Magnus, Head of Medical Sequencing, Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, The Centre for Applied Genomics, Toronto, The Hospital for sick children [Toronto] (SickKids)-University of Toronto-Department of Molecular Genetics-McLaughlin Centre, Carolina Institute for Developmental Disabilities, Analytic and Translational Genetics Unit, Rush University Medical Center [Chicago], Julius-Maximilians-Universität Würzburg (JMU), Washington University in Saint Louis (WUSTL), Department of Statistics, Carnegie Mellon University [Pittsburgh] (CMU), Department of Experimental Clinical and Health Psychology, Universiteit Gent = Ghent University (UGENT), Department of Child and Adolescent Psychiatry, Georg-August-University = Georg-August-Universität Göttingen, Department of Medicine, Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM)-Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Departments of Psychiatry and Genetics, Yale School of Medicine [New Haven, Connecticut] (YSM), Maine Medical Center, Free University of Amsterdam, Department of Psychiatry and Behavioral Sciences [Stanford], Pathology and Laboratory Medicine, The Scripps Translational Science Institute and The Scripps Research Institute, Psychiatric Center Nordbaden, Division of Cancer Epidemiology and Genetics, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), The Scripps Translational Science Institute and Scripps Health, Child and Adolescent Psychiatry, Aarhus University Hospital, Molecular Neuropsychiatry and Development Laboratory, Department of Molecular Physiology & Biophysics and Psychiatry, Vanderbilt University [Nashville]-Centers for Human Genetics Research and Molecular Neuroscience, Department of Psychiatry and Behavioural Neurosciences, McMaster University [Hamilton, Ontario]-Offord Centre for Child Studies, The Translational Genomics Research Institute (TGen), Oxford Health NHS Foundation Trust, Marlborough House Secure Unit, Instituto Nacional de Saùde Dr Ricardo Jorge [Portugal] (INSA), BioFIG, Center for Biodiversity, Functional and Integrative Genomics, Battelle Center for Mathematical Medicine, Ohio State University [Columbus] (OSU)-Nationwide Children's Hospital, University of Toronto, Diamantina Institute, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Departments of Biostatistics and Medicine, University of Washington [Seattle], ArcelorMittal Maizières Research SA, ArcelorMittal, Institute of Mental Health, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU)-Johns Hopkins University (JHU), Psychiatrie & Neuropsychologie, Farmacologie en Toxicologie, RS: CARIM School for Cardiovascular Diseases, RS: MHeNs School for Mental Health and Neuroscience, Biological Psychology, Educational Neuroscience, Clinical Neuropsychology, Neuroscience Campus Amsterdam - Brain Mechanisms in Health & Disease, LEARN! - Social cognition and learning, Biophotonics and Medical Imaging, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, LEARN! - Brain, learning and development, EMGO+ - Mental Health, LEARN!, Neuroscience Campus Amsterdam - Brain Imaging Technology, LaserLaB - Biophotonics and Microscopy, State University of New York (SUNY)-State University of New York (SUNY), Department of Neuroscience and Physiology, Faculty of Land and Environment, Biosciences Research Division, Department of Environment and Primary Industries Victoria, Department of Epidemiology and Biostatistics, University of California [San Francisco] (UCSF), University of California-University of California, Universität Heidelberg [Heidelberg], Cornell University [New York]-Weill Medical College of Cornell University [New York], Bioinformatics, Internal Medicine, Portland Va Medical Center : Ganzini Linda MD, Technische Universität Dresden = Dresden University of Technology (TU Dresden)-University Hospital Carl Gustav Carus, Centro Nacional de Análisis Genómico (CNAG), Parc Científic de Barcelona (PCB), University of Pennsylvania [Philadelphia], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Division Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, Radboud university [Nijmegen]-Radboud university [Nijmegen], University of California [Irvine] (UCI), University of California-University of California-University of California [Los Angeles] (UCLA), University of Bonn, University of California-University of California-David Geffen School of Medicine [Los Angeles], Cardiff University-Medical Research Council, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia]-Children’s Hospital of Philadelphia (CHOP ), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Oxford [Oxford], Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], University of Toronto-The Hospital for sick children [Toronto] (SickKids)-Department of Molecular Genetics-McLaughlin Centre, Julius-Maximilians-Universität Würzburg [Wurtzbourg, Allemagne] (JMU), Universiteit Gent = Ghent University [Belgium] (UGENT), University of Göttingen - Georg-August-Universität Göttingen, Yale University School of Medicine, Georg-August-University [Göttingen], ANS - Amsterdam Neuroscience, Adult Psychiatry, Child Psychiatry, Psychiatry, Human genetics, NCA - Brain mechanisms in health and disease, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Lee SH, Ripke S, Neale BM, Faraone SV, Purcell SM, Perlis RH, Mowry BJ, Thapar A, Goddard ME, Witte JS, Absher D, Agartz I, Akil H, Amin F, Andreassen OA, Anjorin A, Anney R, Anttila V, Arking DE, Asherson P, Azevedo MH, Backlund L, Badner JA, Bailey AJ, Banaschewski T, Barchas JD, Barnes MR, Barrett TB, Bass N, Battaglia A, Bauer M, Bayés M, Bellivier F, Bergen SE, Berrettini W, Betancur C, Bettecken T, Biederman J, Binder EB, Black DW, Blackwood DH, Bloss CS, Boehnke M, Boomsma DI, Breen G, Breuer R, Bruggeman R, Cormican P, Buccola NG, Buitelaar JK, Bunney WE, Buxbaum JD, Byerley WF, Byrne EM, Caesar S, Cahn W, Cantor RM, Casas M, Chakravarti A, Chambert K, Choudhury K, Cichon S, Cloninger CR, Collier DA, Cook EH, Coon H, Cormand B, Corvin A, Coryell WH, Craig DW, Craig IW, Crosbie J, Cuccaro ML, Curtis D, Czamara D, Datta S, Dawson G, Day R, De Geus EJ, Degenhardt F, Djurovic S, Donohoe GJ, Doyle AE, Duan J, Dudbridge F, Duketis E, Ebstein RP, Edenberg HJ, Elia J, Ennis S, Etain B, Fanous A, Farmer AE, Ferrier IN, Flickinger M, Fombonne E, Foroud T, Frank J, Franke B, Fraser C, Freedman R, Freimer NB, Freitag CM, Friedl M, Frisén L, Gallagher L, Gejman PV, Georgieva L, Gershon ES, Geschwind DH, Giegling I, Gill M, Gordon SD, Gordon-Smith K, Green EK, Greenwood TA, Grice DE, Gross M, Grozeva D, Guan W, Gurling H, De Haan L, Haines JL, Hakonarson H, Hallmayer J, Hamilton SP, Hamshere ML, Hansen TF, Hartmann AM, Hautzinger M, Heath AC, Henders AK, Herms S, Hickie IB, Hipolito M, Hoefels S, Holmans PA, Holsboer F, Hoogendijk WJ, Hottenga JJ, Hultman CM, Hus V, Ingason A, Ising M, Jamain S, Jones EG, Jones I, Jones L, Tzeng JY, Kähler AK, Kahn RS, Kandaswamy R, Keller MC, Kennedy JL, Kenny E, Kent L, Kim Y, Kirov GK, Klauck SM, Klei L, Knowles JA, Kohli MA, Koller DL, Konte B, Korszun A, Krabbendam L, Krasucki R, Kuntsi J, Kwan P, Landén M, Långström N, Lathrop M, Lawrence J, Lawson WB, Leboyer M, Ledbetter DH, Lee PH, Lencz T, Lesch KP, Levinson DF, Lewis CM, Li J, Lichtenstein P, Lieberman JA, Lin DY, Linszen DH, Liu C, Lohoff FW, Loo SK, Lord C, Lowe JK, Lucae S, MacIntyre DJ, Madden PA, Maestrini E, Magnusson PK, Mahon PB, Maier W, Malhotra AK, Mane SM, Martin CL, Martin NG, Mattheisen M, Matthews K, Mattingsdal M, McCarroll SA, McGhee KA, McGough JJ, McGrath PJ, McGuffin P, McInnis MG, McIntosh A, McKinney R, McLean AW, McMahon FJ, McMahon WM, McQuillin A, Medeiros H, Medland SE, Meier S, Melle I, Meng F, Meyer J, Middeldorp CM, Middleton L, Milanova V, Miranda A, Monaco AP, Montgomery GW, Moran JL, Moreno-De-Luca D, Morken G, Morris DW, Morrow EM, Moskvina V, Muglia P, Mühleisen TW, Muir WJ, Müller-Myhsok B, Murtha M, Myers RM, Myin-Germeys I, Neale MC, Nelson SF, Nievergelt CM, Nikolov I, Nimgaonkar V, Nolen WA, Nöthen MM, Nurnberger JI, Nwulia EA, Nyholt DR, O'Dushlaine C, Oades RD, Olincy A, Oliveira G, Olsen L, Ophoff RA, Osby U, Owen MJ, Palotie A, Parr JR, Paterson AD, Pato CN, Pato MT, Penninx BW, Pergadia ML, Pericak-Vance MA, Pickard BS, Pimm J, Piven J, Posthuma D, Potash JB, Poustka F, Propping P, Puri V, Quested DJ, Quinn EM, Ramos-Quiroga JA, Rasmussen HB, Raychaudhuri S, Rehnström K, Reif A, Ribasés M, Rice JP, Rietschel M, Roeder K, Roeyers H, Rossin L, Rothenberger A, Rouleau G, Ruderfer D, Rujescu D, Sanders AR, Sanders SJ, Santangelo SL, Sergeant JA, Schachar R, Schalling M, Schatzberg AF, Scheftner WA, Schellenberg GD, Scherer SW, Schork NJ, Schulze TG, Schumacher J, Schwarz M, Scolnick E, Scott LJ, Shi J, Shilling PD, Shyn SI, Silverman JM, Slager SL, Smalley SL, Smit JH, Smith EN, Sonuga-Barke EJ, St Clair D, State M, Steffens M, Steinhausen HC, Strauss JS, Strohmaier J, Stroup TS, Sutcliffe JS, Szatmari P, Szelinger S, Thirumalai S, Thompson RC, Todorov AA, Tozzi F, Treutlein J, Uhr M, van den Oord EJ, Van Grootheest G, Van Os J, Vicente AM, Vieland VJ, Vincent JB, Visscher PM, Walsh CA, Wassink TH, Watson SJ, Weissman MM, Werge T, Wienker TF, Wijsman EM, Willemsen G, Williams N, Willsey AJ, Witt SH, Xu W, Young AH, Yu TW, Zammit S, Zandi PP, Zhang P, Zitman FG, Zöllner S, Devlin B, Kelsoe JR, Sklar P, Daly MJ, O'Donovan MC, Craddock N, Sullivan PF, Smoller JW, Kendler KS, Wray NR, Cardiff University-Medical Research Council (MRC), HudsonAlpha Institute for Biotechnology, The Institute of Psychiatry-King‘s College London, Cornell University-Weill Medical College of Cornell University [New York], Stanford University Medical School, Technische Universität Dresden (TUD)-University Hospital Carl Gustav Carus, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Hôpital Albert Chenevier, McGill University-Montreal Children's Hospital, Universidade Federal do Rio de Janeiro [Rio de Janeiro] (UFRJ), Stanford University School of Medicine [Stanford], Stanford University [Stanford], Eberhard Karls Universität Tübingen, Friedrich Alexander University [Erlangen-Nürnberg], Università di Bologna [Bologna] (UNIBO), University of Toronto-The Hospital for Sick Children-Department of Molecular Genetics-McLaughlin Centre, Washington University School of Medicine, Ghent University [Belgium] (UGENT), University of Goettingen, CHUM Research Center, Psychiatry and Behavioral Science, Stanford University School of Medicine [CA, USA], Aalborg Psychiatric Hospital, Aarhus University Hospital, Washington University in St Louis, Instituto Nacional de Saude Dr Ricardo Jorge, Oades, Robert D., Guellaen, Georges, Medical Oncology, Epidemiology, Child and Adolescent Psychiatry / Psychology, and Hematology
Subjects: Netherlands Twin Register (NTR), Medizin, Inheritance Patterns, Social Sciences, AUTISM SPECTRUM DISORDERS, nosology, heritability, COMMON SNPS, 0302 clinical medicine, Crohn Disease, SCHIZOPHRENIA, Child, Psychiatric genetics, Genetics & Heredity, MAJOR DEPRESSIVE DISORDER, RISK, 0303 health sciences, ATTENTION-DEFICIT/HYPERACTIVITY DISORDER, 120 000 Neuronal Coherence, Mental Disorders, Variants, BIPOLAR DISORDER, ASSOCIATION, Genomic disorders and inherited multi-system disorders [DCN PAC - Perception action and control IGMD 3], Psychiatric Disorders, CROHNS-DISEASE, 3. Good health, Schizophrenia, genetic association study, Medical genetics, Major depressive disorder, SNPs, Adult, medicine.medical_specialty, genetic etiology, medical genetics, DEFICIT HYPERACTIVITY DISORDER, Biology, Polymorphism, Single Nucleotide, behavioral disciplines and activities, Article, Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory [IGMD 3], Heritability, Genetic Heterogeneity, 03 medical and health sciences, Prevalence of mental disorders, mental disorders, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Genetics, medicine, ddc:61, Humans, Attention deficit hyperactivity disorder, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, DCN PAC - Perception action and control NCEBP 9 - Mental health, ddc:610, Medizinische Fakultät » Universitätsklinikum Essen » LVR-Klinikum Essen » Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Bipolar disorder, Psychiatry, 030304 developmental biology, Depressive Disorder, Major, Genome, Human, Genetic heterogeneity, medicine.disease, schizophrenia, Attention Deficit Disorder with Hyperactivity, Child Development Disorders, Pervasive, Perturbações do Desenvolvimento Infantil e Saúde Mental, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: AM Vicente - Cross-Disorder Group of the Psychiatric Genomics Consortium Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.
Published: 2013

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