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6 results on '"Milena Radivojkov-Blagojevic"'

1. Biallelic loss‐of‐function variants in RBL2 in siblings with a neurodevelopmental disorder

Author

Theresa Brunet, Milena Radivojkov‐Blagojevic, Peter Lichtner, Verena Kraus, Thomas Meitinger, and Matias Wagner

Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract The RBL2 locus has been associated with intelligence and educational attainment but not with a monogenic disorder to date. RBL2 encodes p130, a member of the retinoblastoma protein family, which is involved in mediating neuron survival and death. Previous studies on p130 knockout mice revealing embryonic death and impaired neurogenesis underscore the importance of RBL2 in brain development. Exome sequencing in two siblings with severe intellectual disability, stereotypies and dysmorphic features identified biallelic loss‐of‐function variants c.556C>T, p.(Arg186Ter) and a deletion of exon 13–17 in RBL2 (NM_005611.3), establishing RBL2 as a candidate gene for an autosomal recessive neurodevelopmental disorder.

Published
2020
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2. Mendelian Randomisation Study of Smoking, Alcohol, and Coffee Drinking in Relation to Parkinson’s Disease

Author

Athina Simitsi, Grazia Annesi, Hirotaka Matsuo, Leonor Correia Guedes, Mario Ezquerra, Kenya Nishioka, Ashwin Ashok Kumar Sreelatha, Simona Petrucci, Dimitri Krainc, Angela Deutschländer, Ekaterina Rogaeva, Lasse Pihlstrøm, Manu Sharma, Thomas Gasser, Mathias Toft, Jan O. Aasly, Cloé Domenighetti, Monica Diez-Fairen, Milena Radivojkov-Blagojevic, Sandeep Grover, Andrew B. Singleton, Bart P.C. van de Warrenburg, Yun Joong Kim, Andrea Quattrone, Sun Ju Chung, Gianni Pezzoli, Pierre-Emmanuel Sugier, Sulev Kõks, Lena F. Burbulla, Jonathan Carr, Walter Pirker, Efthimos Dardiotis, Karin Wirdefeldt, George D. Mellick, Jean-Christophe Corvol, Dheeraj Reddy Bobbili, Anthony E. Lang, Eugénie Mutez, Georges M. Hadjigeorgiou, Anna Zecchinelli, Laura Brighina, Connor Edsall, Océane Mohamed, Berta Portugal, Andreas Puschmann, Nancy L. Pedersen, Alexander Zimprich, Patrick May, Matthew J. Farrer, Leonidas Stefanis, Yusuke Kawamura, Eduardo Tolosa, Claudia Schulte, Alexis Brice, Caroline Ran, Manuela Tan, Pille Taba, Peter Lichtner, Alexis Elbaz, Dena G. Hernandez, Monica Gagliardi, Andrea Carmine Belin, Joaquim J. Ferreira, Suzanne Lesage, Pierre Kolber, Kathrin Brockmann, Marie-Christine Chartier-Harlin, Carl E Clarke, Karen E. Morrison, Nobutaka Hattori, Stefano Duga, Letizia Straniero, Rejko Krüger, Carlo Ferrarese, Pau Pastor, Soraya Bardien, Clara Hellberg, Bastiaan R. Bloem, Enza Maria Valente, Domenighetti, C, Sugier, P, Sreelatha, A, Schulte, C, Grover, S, Mohamed, O, Portugal, B, May, P, Bobbili, D, Radivojkov-Blagojevic, M, Lichtner, P, Singleton, A, Hernandez, D, Edsall, C, Mellick, G, Zimprich, A, Pirker, W, Rogaeva, E, Lang, A, Koks, S, Taba, P, Lesage, S, Brice, A, Corvol, J, Chartier-Harlin, M, Mutez, E, Brockmann, K, Deutschlander, A, Hadjigeorgiou, G, Dardiotis, E, Stefanis, L, Simitsi, A, Valente, E, Petrucci, S, Duga, S, Straniero, L, Zecchinelli, A, Pezzoli, G, Brighina, L, Ferrarese, C, Annesi, G, Quattrone, A, Gagliardi, M, Matsuo, H, Kawamura, Y, Hattori, N, Nishioka, K, Chung, S, Kim, Y, Kolber, P, Van De Warrenburg, B, Bloem, B, Aasly, J, Toft, M, Pihlstrom, L, Guedes, L, Ferreira, J, Bardien, S, Carr, J, Tolosa, E, Ezquerra, M, Pastor, P, Diez-Fairen, M, Wirdefeldt, K, Pedersen, N, Ran, C, Belin, A, Puschmann, A, Hellberg, C, Clarke, C, Morrison, K, Tan, M, Krainc, D, Burbulla, L, Farrer, M, Kruger, R, Gasser, T, Sharma, M, and Elbaz, A

Subjects
Inverse Association, Parkinson's disease, parkinson’s disease, Alcohol Drinking, coffee, Alcohol, Disease, epidemiology [Alcohol Drinking], Coffee, Article, Cellular and Molecular Neuroscience, symbols.namesake, chemistry.chemical_compound, genetics [Parkinson Disease], Risk Factors, epidemiology [Smoking], Humans, Medicine, ddc:610, Coffee drinking, Aged, alcohol, business.industry, Smoking, Confounding, Parkinson Disease, Odds ratio, Mendelian Randomization Analysis, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, mendelian randomisation, chemistry, genetics [Alcohol Drinking], Parkinson’s disease, smoking, aged, alcohol drinking, genome-wide association study, humans, mendelian randomization analysis, risk factors, parkinson disease, Mendelian inheritance, symbols, etiology [Parkinson Disease], Neurology (clinical), business, Genome-Wide Association Study, Demography
Abstract

Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

Published
2022

3. Predicting cardiac electrical response to sodium-channel blockade and Brugada syndrome using polygenic risk scores

Author

Hanno L. Tan, Sulayman el Mathari, Thomas Meitinger, Leander Beekman, Michael W.T. Tanck, Jan A. Kors, Ahmad S. Amin, Milena Radivojkov-Blagojevic, Rafik Tadros, Arthur A.M. Wilde, Najim Lahrouchi, Connie R. Bezzina, Pieter G. Postema, Medical Informatics, Cardiology, ACS - Heart failure & arrhythmias, Graduate School, Epidemiology and Data Science, and APH - Methodology

Subjects
Male, Genotyping Techniques, Genome-wide association study, 030204 cardiovascular system & hematology, PR, Sodium Channels, Electrocardiography, 0302 clinical medicine, Heart Rate, Family history, Infusions, Intravenous, Brugada syndrome, Brugada Syndrome, 0303 health sciences, education.field_of_study, Ajmaline, Arrhythmia/Electrophysiology, Heart, ddc, 3. Good health, Cardiology, Female, Cardiology and Cardiovascular Medicine, Anti-Arrhythmia Agents, medicine.drug, Sodium Channel Blockers, Genetic Markers, medicine.medical_specialty, Population, QRS, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, QRS complex, Polygenic risk score, Clinical Research, Internal medicine, Clinical Decision Rules, medicine, Humans, cardiovascular diseases, PR interval, education, 030304 developmental biology, Genetic association, Dose-Response Relationship, Drug, business.industry, Sodium, fungi, medicine.disease, Editor's Choice, Polygenic Risk Score, Qrs, Pr, business, Genome-Wide Association Study
Abstract

Aims Sodium-channel blockers (SCBs) are associated with arrhythmia, but variability of cardiac electrical response remains unexplained. We sought to identify predictors of ajmaline-induced PR and QRS changes and Type I Brugada syndrome (BrS) electrocardiogram (ECG). Methods and results In 1368 patients that underwent ajmaline infusion for suspected BrS, we performed measurements of 26 721 ECGs, dose–response mixed modelling and genotyping. We calculated polygenic risk scores (PRS) for PR interval (PRSPR), QRS duration (PRSQRS), and Brugada syndrome (PRSBrS) derived from published genome-wide association studies and used regression analysis to identify predictors of ajmaline dose related PR change (slope) and QRS slope. We derived and validated using bootstrapping a predictive model for ajmaline-induced Type I BrS ECG. Higher PRSPR, baseline PR, and female sex are associated with more pronounced PR slope, while PRSQRS and age are positively associated with QRS slope (P Conclusion We show for the first time that genetic factors underlie the variability of cardiac electrical response to SCB. PRSBrS, family history, and a baseline ECG can predict the development of a diagnostic drug-induced Type I BrS ECG with clinically relevant accuracy. These findings could lead to the use of PRS in the diagnosis of BrS and, if confirmed in population studies, to identify patients at risk for toxicity when given SCB.

Published
2019

4. Synthetic AAV/CRISPR vectors for blocking HIV-1 expression in persistently infected astrocytes

Author

Dirk Grimm, Kathleen Börner, Ruth Brack-Werner, Micha Drukker, Martha Schneider, Sabrina C. Desbordes, Tanja Orschmann, Ejona Rusha, Christine Kunze, Milena Radivojkov-Blagojevic, and Eike Kienle

Subjects
0301 basic medicine, Gene Expression Regulation, Viral, Male, Foreskin, Genetic Vectors, Gene delivery, Biology, Virus, 03 medical and health sciences, Cellular and Molecular Neuroscience, Transduction (genetics), 0302 clinical medicine, Transcriptional regulation, medicine, CRISPR, Humans, Clustered Regularly Interspaced Short Palindromic Repeats, Gene, Cells, Cultured, Cell Line, Transformed, Cas9, Dependovirus, Virology, 030104 developmental biology, medicine.anatomical_structure, HEK293 Cells, Neurology, Astrocytes, HIV-1, 030217 neurology & neurosurgery, Astrocyte
Abstract

Astrocytes, the most abundant cells in the mammalian brain, perform key functions and are involved in several neurodegenerative diseases. The human immunodeficiency virus (HIV) can persist in astrocytes, contributing to the HIV burden and neurological dysfunctions in infected individuals. While a comprehensive approach to HIV cure must include the targeting of HIV-1 in astrocytes, dedicated tools for this purpose are still lacking. Here we report a novel Adeno-associated virus-based vector (AAV9P1) with a synthetic surface peptide for transduction of astrocytes. Analysis of AAV9P1 transduction efficiencies with single brain cell populations, including primary human brain cells, as well as human brain organoids demonstrated that AAV9P1 targeted terminally differentiated human astrocytes much more efficiently than neurons. We then investigated whether AAV9P1 can be used to deliver HIV-inhibitory genes to astrocytes. To this end we generated AAV9P1 vectors containing genes for HIV-1 proviral editing by CRISPR/Cas9. Latently HIV-1 infected astrocytes transduced with these vectors showed significantly diminished reactivation of proviruses, compared with untransduced cultures. Sequence analysis identified mutations/deletions in key HIV-1 transcriptional control regions. We conclude that AAV9P1 is a promising tool for gene delivery to astrocytes and may facilitate inactivation/destruction of persisting HIV-1 proviruses in astrocyte reservoirs.

Published
2017

5. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis

Author

Aleksey Shatunov, An Goris, John Hardy, Thomas F. Meyer, Sandra D'Alfonso, Christian A. Hübner, Karol Estrada, Susana Pinto, Cristina Moglia, Perry T.C. van Doormaal, Simona Arcuti, Thomas Meitinger, Siddharthan Chandran, Kim A. Staats, Cinzia Bertolin, Peter M. Andersen, Ricardo Rojas-García, William Sproviero, Katie Sidle, François Salachas, Robert Swingler, Anna M. Blokhuis, Thomas M. Ringer, Emily P. McCann, Garth A. Nicholson, Lude Franke, Sven Cichon, Julian Grosskreutz, Markus M. Nöthen, Bernhard Landwehrmeyer, Lukas Tittmann, Jennifer A. Fifita, Christian R. Andres, Alice Vajda, Viviana Pensato, Lauren Elman, Gijs H.P. Tazelaar, Christian Lunetta, Patrick Vourc'h, Christopher Shaw, Gilbert Bensimon, Orla Hardiman, Kuang Lin, Pamela J. Shaw, Alessandro Padovani, Massimiliano Filosto, Jan H. Veldink, Boris Rogelj, Giacomo P. Comi, Matthew C. Kiernan, Philippe Corcia, Giancarlo Logroscino, Ammar Al-Chalabi, Blaž Koritnik, Safaa Saker-Delye, Ian P. Blair, Alexis Brice, Jochen H. Weishaupt, Gianni Sorarù, Maura Brunetti, Alan M. Pittman, Vincenzo Silani, Cindy Maurel, Alexandra Durr, Catherine Lomen-Hoerth, Matthew R. Robinson, Russell L. McLaughlin, Martina Wiedau-Pazos, Chiara Zecca, Nilo Riva, Ashley R. Jones, Andre Franke, Tune H. Pers, Roberto Del Bo, Dominic B. Rowe, Susanne Petri, Sara L. Pulit, John Q. Trojanowski, Wim Robberecht, Christine Payan, Otto W. Witte, Katharine Y. Zhang, Jesus S. Mora, Rick A.A. van der Spek, Urmo Võsa, Kevin P. Kenna, Marcella Rietschel, Milena Radivojkov-Blagojevic, Tino Prell, Philip Van Damme, Leja Dolenc Grošelj, Androniki Menelaou, Beatrice Stubendorff, Cristina Cereda, Kristel R. van Eijk, Leo McCluskey, Jean-François Dartigues, Rosa Capozzo, Markus Weber, Cinzia Tiloca, Michael A. van Es, Wouter van Rheenen, Paul I.W. de Bakker, Carsten Drepper, Bradley N. Smith, Ettore Beghi, Jian Yang, Peter M. Visscher, Hamid Hamzeiy, John Landers, A. Nazli Basak, Hylke M. Blauw, Annelot M. Dekker, Richard W. Orrell, Silvana Penco, Fernando Rivadeneira, Marianne de Visser, Ceren Tunca, Cathryn M. Lewis, Vincent Meininger, Andrea Malaspina, Raymond D. Schellevis, Leonard H. van den Berg, Rosanna Tortelli, Shuna Colville, Anneke J. van der Kooi, Ingo Kurth, Roger Pamphlett, Stéphanie Millecamps, Janez Zidar, Michael Sendtner, Simone de Jong, Roel A. Ophoff, Mamede de Carvalho, Karen E. Morrison, Robbert Jan Stuit, Letizia Mazzini, Jonathan D. Glass, Yesim Parman, Albert Hofman, Lea Leonardis, Naomi R. Wray, Meraida Polak, William J. Brands, Susanne Abdulla, Bernard Muller, Cinzia Gellera, Max Koppers, Pietro Fratta, John Powell, Charles Curtis, Peter Lichtner, Frank P. Diekstra, Adriano Chiò, Isabella Fogh, Federico Casale, Nicholas W. Wood, Katarina Vrabec, André G. Uitterlinden, Vivianna M. Van Deerlin, Gerome Breen, Wolfgang Lieb, Oliver Harschnitz, Nicola Ticozzi, P. Nigel Leigh, R. Jeroen Pasterkamp, Simon Topp, Metka Ravnik-Glavač, Christophe Tzourio, Robert H. Brown, Andrea Calvo, Orietta Pansarasa, Jelena Medic, Albert C. Ludolph, Elisabetta Pupillo, Antonia Ratti, Philippe Amouyel, Repositório da Universidade de Lisboa, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), Stem Cell Aging Leukemia and Lymphoma (SALL), Erasmus MC other, Pediatric Surgery, Internal Medicine, Epidemiology, Neurology, and ANS - Neurodegeneration

Subjects
0301 basic medicine, Population, EFFICIENT, Genome-wide association study, Locus (genetics), Biology, SUSCEPTIBILITY, SEQUENCE, Article, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Munc18 Proteins, medicine, Journal Article, Genetics, Humans, Genetic Predisposition to Disease, Comparative Study, Amyotrophic lateral sclerosis, education, POPULATION, Genetic association, Netherlands, PITFALLS, education.field_of_study, HEXANUCLEOTIDE REPEAT, COMPLEX, Project MinE, Amyotrophic Lateral Sclerosis, Proteins, PATHWAYS, FRONTOTEMPORAL DEMENTIA, medicine.disease, Genetic architecture, Cytoskeletal Proteins, 030104 developmental biology, Case-Control Studies, Mutation, ALS, 030217 neurology & neurosurgery, Imputation (genetics), Myelin Proteins, Genome-Wide Association Study
Abstract

Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved., To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Published
2016

6. Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Author

Uwe K. Zettl, Michael Pütz, Rajesh Rawal, Frauke Zipp, Martin Stangel, Ulf Schminke, Marcus Ising, Martina Müller-Nurasyid, Heinz Wiendl, Jürgen Haas, Thomas Meitinger, Michael Hecker, Wolfgang Lieb, Magdalena Zoledziewska, Tania Carrillo-Roa, Ulf Ziemann, S. Nischwitz, Stefan Herms, Maristella Pitzalis, Stefan Kloiber, Frank Weber, Hayrettin Tumani, Bertram Müller-Myhsok, Sven G. Meuth, Georg Homuth, Ralf Gold, M. Knop, Antonella Mulas, Christina M. Lill, Henry Völzke, Antonios Bayas, Francesco Cucca, Eleonora Porcu, Andrew T. Chan, Janine Arloth, Lukas Bechmann, Darina Czamara, Dorothea Buck, Klaus Berger, Peter Lichtner, Jürgen Wellmann, Susanne Moebus, Andre Franke, Florian Then Bergh, Peter Weber, Thomas Bettecken, Ilenia Zara, Till F. M. Andlauer, Volker Limmroth, Achim Berthele, Ralf A. Linker, Tobias Ruck, Anke Salmen, Matthias Laudes, Gisela Antony, Christiane Graetz, Christian Gieger, Konstantin Strauch, Astrid Petersmann, Elisabeth B. Binder, Melanie Waldenberger, Christiane Gasperi, Carlo Sidore, Brigitte Wildemann, Friedemann Paul, Felix Luessi, Bernhard Hemmer, Klarissa Hanja Stürner, Karl-Heinz Jöckel, Milena Radivojkov-Blagojevic, Björn Tackenberg, Tim Kacprowski, Lars Bertram, Clemens Warnke, Markus O. Scheinhardt, Theresa Dankowski, Verena Loleit, Tania Kümpfel, Carmen Infante-Duarte, Susanne Lucae, Markus M. Nöthen, Jan-Patrick Stellmann, Mark Mühlau, and Andreas Ziegler

Subjects
0301 basic medicine, Male, DLEU1, Medizin, Genome-wide association study, Epigenesis, Genetic, Cohort Studies, Research Articles, Transcriptional Regulator ERG, Genetics, Aged, 80 and over, Glycine Hydroxymethyltransferase, education.field_of_study, Multidisciplinary, DNA methylation, SciAdv r-articles, Middle Aged, SHMT1, 3. Good health, ddc, DNA-Binding Proteins, ERG, Female, MAZ, Function and Dysfunction of the Nervous System, Research Article, Adult, Adolescent, Population, Quantitative Trait Loci, 610 Medicine & health, Dleu1, Dna Methylation, Erg, L3mbtl3, Maz, Multiple Sclerosis, Shmt1, Genome-wide Association Study, Quantitative trait locus, Biology, Major histocompatibility complex, Neurological Disorders, Multiple sclerosis, 03 medical and health sciences, Young Adult, Humans, Genetic Predisposition to Disease, L3MBTL3, Epigenetics, Allele, education, Alleles, Aged, genome-wide association study, 030104 developmental biology, Genetic Loci, Case-Control Studies, biology.protein, Transcription Factors
Abstract

Genome-wide study in Germans identifies four novel multiple sclerosis risk genes and confirms already known gene loci., We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

Published
2016

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