1,535 results on '"Wolfram S"'
Search Results
152. Reflectance as an indirect measurement of the extent of laser-induced coagulation.
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Youli Yang, Michael S. Markow, H. Grady Rylander III, Wolfram S. Weinberg, and Ashley J. Welch
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- 1990
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153. Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy
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Stenton, Sarah L., primary, Sheremet, Natalia L., additional, Catarino, Claudia B., additional, Andreeva, Natalia A., additional, Assouline, Zahra, additional, Barboni, Piero, additional, Barel, Ortal, additional, Berutti, Riccardo, additional, Bychkov, Igor, additional, Caporali, Leonardo, additional, Capristo, Mariantonietta, additional, Carbonelli, Michele, additional, Cascavilla, Maria L., additional, Charbel Issa, Peter, additional, Freisinger, Peter, additional, Gerber, Sylvie, additional, Ghezzi, Daniele, additional, Graf, Elisabeth, additional, Heidler, Juliana, additional, Hempel, Maja, additional, Heon, Elise, additional, Itkis, Yulya S., additional, Javasky, Elisheva, additional, Kaplan, Josseline, additional, Kopajtich, Robert, additional, Kornblum, Cornelia, additional, Kovacs-Nagy, Reka, additional, Krylova, Tatiana D., additional, Kunz, Wolfram S., additional, La Morgia, Chiara, additional, Lamperti, Costanza, additional, Ludwig, Christina, additional, Malacarne, Pedro F., additional, Maresca, Alessandra, additional, Mayr, Johannes A., additional, Meisterknecht, Jana, additional, Nevinitsyna, Tatiana A., additional, Palombo, Flavia, additional, Pode-Shakked, Ben, additional, Shmelkova, Maria S., additional, Strom, Tim M., additional, Tagliavini, Francesca, additional, Tzadok, Michal, additional, van der Ven, Amelie T., additional, Vignal-Clermont, Catherine, additional, Wagner, Matias, additional, Zakharova, Ekaterina Y., additional, Zhorzholadze, Nino V., additional, Rozet, Jean-Michel, additional, Carelli, Valerio, additional, Tsygankova, Polina G., additional, Klopstock, Thomas, additional, Wittig, Ilka, additional, and Prokisch, Holger, additional
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- 2021
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154. Novel KCNH1 Mutations Associated with Epilepsy: Broadening the Phenotypic Spectrum of KCNH1-Associated Diseases
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von Wrede, Randi, primary, Jeub, Monika, additional, Ariöz, Idil, additional, Elger, Christian E., additional, von Voss, Hubertus, additional, Klein, Hanns-Georg, additional, Becker, Albert J., additional, Schoch, Susanne, additional, Surges, Rainer, additional, and Kunz, Wolfram S., additional
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- 2021
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155. Open Discussion on A Computable Universe
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Bauer, A., primary, Bolognesi, T., additional, Cabello, A., additional, Calude, C. S., additional, De Mol, L., additional, Doria, F., additional, Fredkin, E., additional, Hewitt, C., additional, Hutter, M., additional, Margenstern, M., additional, Svozil, K., additional, Szudzik, M., additional, Teuscher, C., additional, Wolfram, S., additional, and Zenil, H., additional
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- 2012
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156. Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A
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Kasperavičiūtė, Dalia, Catarino, Claudia B., Matarin, Mar, Leu, Costin, Novy, Jan, Tostevin, Anna, Leal, Bárbara, Hessel, Ellen V. S., Hallmann, Kerstin, Hildebrand, Michael S., Dahl, Hans-Henrik M., Ryten, Mina, Trabzuni, Daniah, Ramasamy, Adaikalavan, Alhusaini, Saud, Doherty, Colin P., Dorn, Thomas, Hansen, Jörg, Krämer, Günter, Steinhoff, Bernhard J., Zumsteg, Dominik, Duncan, Susan, Kälviäinen, Reetta K., Eriksson, Kai J., Kantanen, Anne-Mari, Pandolfo, Massimo, Gruber-Sedlmayr, Ursula, Schlachter, Kurt, Reinthaler, Eva M., Stogmann, Elisabeth, Zimprich, Fritz, Théâtre, Emilie, Smith, Colin, O’Brien, Terence J., Meng Tan, K., Petrovski, Slave, Robbiano, Angela, Paravidino, Roberta, Zara, Federico, Striano, Pasquale, Sperling, Michael R., Buono, Russell J., Hakonarson, Hakon, Chaves, João, Costa, Paulo P., Silva, Berta M., da Silva, António M., de Graan, Pierre N. E., Koeleman, Bobby P. C., Becker, Albert, Schoch, Susanne, von Lehe, Marec, Reif, Philipp S., Rosenow, Felix, Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Rössler, Karl, Buchfelder, Michael, Hamer, Hajo M., Kobow, Katja, Coras, Roland, Blumcke, Ingmar, Scheffer, Ingrid E., Berkovic, Samuel F., Weale, Michael E., Delanty, Norman, Depondt, Chantal, Cavalleri, Gianpiero L., Kunz, Wolfram S., and Sisodiya, Sanjay M.
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- 2013
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157. SONOGRAPHY OF THE MEDIAN NERVE IN CMT1A, CMT2A, CMTX, AND HNPP
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Schreiber, Stefanie, Oldag, Andreas, Kornblum, Cornelia, Kollewe, Katja, Kropf, Siegfried, Schoenfeld, Ariel, Feistner, Helmut, Jakubiczka, Sibylle, Kunz, Wolfram S., Scherlach, Cordula, Tempelmann, Claus, Mawrin, Christian, Dengler, Reinhard, Schreiber, Frank, Goertler, Michael, and Vielhaber, Stefan
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- 2013
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158. Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy
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Mller, Rikke S., Weber, Yvonne G., Klitten, Laura L., Trucks, Holger, Muhle, Hiltrud, Kunz, Wolfram S., Mefford, Heather C., Franke, Andre, Kautza, Monika, Wolf, Peter, Dennig, Dieter, Schreiber, Stefan, Rückert, Ina-Maria, Wichmann, H.-Erich, Ernst, Jan P., Schurmann, Claudia, Grabe, Hans J., Tommerup, Niels, Stephani, Ulrich, Lerche, Holger, Hjalgrim, Helle, Helbig, Ingo, and Sander, Thomas
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- 2013
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159. Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy
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Lal, Dennis, Trucks, Holger, Mller, Rikke S., Hjalgrim, Helle, Koeleman, Bobby P. C., de Kovel, Carolien G. F., Visscher, Frank, Weber, Yvonne G., Lerche, Holger, Becker, Felicitas, Schankin, Christoph J., Neubauer, Bernd A., Surges, Rainer, Kunz, Wolfram S., Zimprich, Fritz, Franke, Andre, Illig, Thomas, Ried, Janina S., Leu, Costin, Nürnberg, Peter, and Sander, Thomas
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- 2013
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160. Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam
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Helmstaedter, Christoph, Mihov, Yoan, Toliat, Mohammad R., Thiele, Holger, Nuernberg, Peter, Schoch, Susanne, Surges, Rainer, Elger, Christian E., Kunz, Wolfram S., and Hurlemann, René
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- 2013
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161. Differences in Flux Control and Reserve Capacity of Cytochrome c Oxidase (COX) in Human Skeletal Muscle and Brain Suggest Different Metabolic Effects of Mild COX Deficiencies
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Kudin, Alexei, Vielhaber, Stefan, Elger, Christian E., and Kunz, Wolfram S.
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- 2002
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162. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With Pathogenic Variants.
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Schwarz, Niklas, Seiffert, Simone, Pendziwiat, Manuela, Rademacher, Annika Verena, Brünger, Tobias, Hedrich, Ulrike B.S., Augustijn, Paul B., Baier, Hartmut, Bayat, Allan, Bisulli, Francesca, Buono, Russell J., Bruria, Ben Zeev, Doyle, Michael G., Guerrini, Renzo, Heimer, Gali, Iacomino, Michele, Kearney, Hugh, Klein, Karl Martin, Kousiappa, Ioanna, and Kunz, Wolfram S.
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- 2022
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163. Binding of copper is a mechanism of homocysteine toxicity leading to COX deficiency and apoptosis in primary neurons, PC12 and SHSY-5Y cells
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Linnebank, Michael, Lutz, Holger, Jarre, Eva, Vielhaber, Stefan, Noelker, Carmen, Struys, Eduard, Jakobs, Cornelis, Klockgether, Thomas, Evert, Bernd O., Kunz, Wolfram S., and Wüllner, Ullrich
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- 2006
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164. In vivo quantification of spinal and bulbar motor neuron degeneration in the G93A-SOD1 transgenic mouse model of ALS by T2 relaxation time and apparent diffusion coefficient
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Niessen, Heiko G., Angenstein, Frank, Sander, Kerstin, Kunz, Wolfram S., Teuchert, Marko, Ludolph, Albert C., Heinze, Hans-Jochen, Scheich, Henning, and Vielhaber, Stefan
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- 2006
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165. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients
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McCormack, Mark, Gui, Hongsheng, Ingason, Andrés, Speed, Doug, Wright, Galen E B, Zhang, Eunice J., Secolin, Rodrigo, Yasuda, Clarissa, Kwok, Maxwell, Wolking, Stefan, Becker, Felicitas, Rau, Sarah, Avbersek, Andreja, Heggeli, Kristin, Leu, Costin, Depondt, Chantal, Sills, Graeme J., Marson, Anthony G., Auce, Pauls, Brodie, Martin J., Francis, Ben, Johnson, Michael R., Koeleman, Bobby P C, Striano, Pasquale, Coppola, Antonietta, Zara, Federico, Kunz, Wolfram S., Sander, Josemir W., Lerche, Holger, Klein, Karl Martin, Weckhuysen, Sarah, Krenn, Martin, Gudmundsson, Lárus J, Stefánsson, Kári, Krause, Roland, Shear, Neil, Ross, Colin J D, Delanty, Norman, Pirmohamed, Munir, Carleton, Bruce C., Cendes, Fernando, Lopes-Cendes, Iscia, Liao, Wei-Ping, O'Brien, Terence J., Sisodiya, Sanjay M., Cherny, Stacey, Kwan, Patrick, Baum, Larry, Cavalleri, Gianpiero L., International League Against Epilepsy Consortium on Complex Epilepsies, Bisulli, Francesca, Mccormack, Mark, Gui, Hongsheng, Ingason, André, Speed, Doug, Wright, Galen E B, Zhang, Eunice J, Secolin, Rodrigo, Yasuda, Clarissa, Kwok, Maxwell, Wolking, Stefan, Becker, Felicita, Rau, Sarah, Avbersek, Andreja, Heggeli, Kristin, Leu, Costin, Depondt, Chantal, Sills, Graeme J, Marson, Anthony G, Auce, Paul, Brodie, Martin J, Francis, Ben, Johnson, Michael R, Koeleman, Bobby P C, Striano, Pasquale, Coppola, Antonietta, Zara, Federico, Kunz, Wolfram S, Sander, Josemir W, Lerche, Holger, Klein, Karl Martin, Weckhuysen, Sarah, Krenn, Martin, Gudmundsson, Lárus J, Stefánsson, Kári, Krause, Roland, Shear, Neil, Ross, Colin J D, Delanty, Norman, Pirmohamed, Munir, Carleton, Bruce C, Cendes, Fernando, Lopes-Cendes, Iscia, Liao, Wei-Ping, O'Brien, Terence J, Sisodiya, Sanjay M, Cherny, Stacey, Kwan, Patrick, Baum, Larry, Cavalleri, Gianpiero L, EPIGEN Consortium, Canadian Pharmacogenomics Network, for the EpiPGX Consortium, Int League Epilepsy Consortium, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Háskóli Íslands, University of Iceland, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, McCormack, Mark, Zhang, Eunice J., Sills, Graeme J., Marson, Anthony G., Brodie, Martin J., Johnson, Michael R., Kunz, Wolfram S., Sander, Josemir W., Carleton, Bruce C., O'Brien, Terence J., Sisodiya, Sanjay M., Cavalleri, Gianpiero L., International League Against Epilepsy Consortium on Complex Epilepsie, and Bisulli, Francesca
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0301 basic medicine ,Linkage disequilibrium ,Pharmacogenomic Variants ,Neurology [D14] [Human health sciences] ,Genome-wide association study ,HLA-A-ASTERISK-3101 ,Linkage Disequilibrium ,0302 clinical medicine ,Flogaveiki ,INDUCED HYPERSENSITIVITY REACTIONS ,Medicine ,genetics ,POPULATION ,education.field_of_study ,Public health ,Taugavísindi ,3. Good health ,Carbamazepine ,Neurology ,Factor H ,Complement Factor H ,Association studies in genetics ,Lýðheilsa ,Anticonvulsants ,Drug Eruptions ,Erfðarannsóknir ,Life Sciences & Biomedicine ,STEVENS-JOHNSON-SYNDROME ,Population ,Antiepileptic drugs ,adverse drug reaction ,Clinical Neurology ,Mutation, Missense ,Human leukocyte antigen ,Complement factor I ,Case control studies ,White People ,Article ,03 medical and health sciences ,Asian People ,RISK-FACTOR ,Seizures ,Genetic variation ,Humans ,GENOME-WIDE ASSOCIATION ,education ,METAANALYSIS ,Retrospective Studies ,Science & Technology ,Neurology & Neurosurgery ,Neurologie [D14] [Sciences de la santé humaine] ,Epilepsy ,HLA-A Antigens ,business.industry ,Genetic Variation ,Correction ,CUTANEOUS ADVERSE-REACTIONS ,1103 Clinical Sciences ,Généralités ,1702 Cognitive Science ,GENOTYPES ,030104 developmental biology ,Apolipoproteins ,Case-Control Studies ,Phenytoin ,LAMOTRIGINE ,Immunology ,Alternative complement pathway ,epilepsy ,Neurosciences & Neurology ,Neurology (clinical) ,Human medicine ,1109 Neurosciences ,business ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Publisher's version (útgefin grein), Objective To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs. Methods We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed. Results We report an association between a rare variant in the complement factor H–related 4 (CFHR4) gene and phenytoin-induced MPE in Europeans (p = 4.5 × 10–11; odds ratio [95% confidence interval] 7 [3.2–16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H (CFH) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients. Conclusions The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H–related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients., This study was not industry-sponsored. The work was supported by a grant from the European Commission (7th Framework Programme Grant 279062, EpiPGX). M.M.C. and G.L.C. are supported by Science Foundation Ireland, grant 13/CDA/2223, and an RCSI seed funding grant GA 14-1899. This project was supported by the General Research Funds (HKU7623/08M and HKU7747/07M to S.C., CUHK4466/06M to P.K.) and Health and Medical Research Fund (HMRF 01120086 to P.K.) from Hong Kong. Some results presented in this article were prepared using the HPC facilities of the University of Luxembourg. This work was partly undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme (J.W.S., S.M.S.). The work was also supported by the Epilepsy Society, UK (J.W.S., S.M.S.), by the foundation “no epilep,” the German Chapter of the ILAE (DGfE) (both to H.L.). F.C. and I.L.-C. are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo, Brazil, through grant 2013/07559-3. J.E.Z. and M.P. thank the NHS Chair of Pharmacogenetics programme and MRC Centre for Drug Safety Science for support in Liverpool. B.C.C. and C.J.D.R. are supported by the Canadian Institutes of Health Research (CIHR) Drug Safety and Effectiveness Network (FRN-117588), the Canada Foundation for Innovation and the Canadian Dermatology Foundation. G.E.B.W. is supported by a CIHR Fellowship. The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. M.M.C., H.G., and G.L.C. had full access to all the data in the study and the corresponding authors had final responsibility for the decision to submit for publication. The Article Processing Charge was funded by the European Commission OpenAIRE2020 project.
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- 2017
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166. Chapter 23 Quantification of Superoxide Production by Mouse Brain and Skeletal Muscle Mitochondria
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Malinska, Dominika, primary, Kudin, Alexei P., additional, Debska-Vielhaber, Grazyna, additional, Vielhaber, Stefan, additional, and Kunz, Wolfram S., additional
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- 2009
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167. Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32
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Steffens, Michael, Leu, Costin, Ruppert, Ann-Kathrin, Zara, Federico, Striano, Pasquale, Robbiano, Angela, Capovilla, Giuseppe, Tinuper, Paolo, Gambardella, Antonio, Bianchi, Amedeo, La Neve, Angela, Crichiutti, Giovanni, de Kovel, Carolien G.F., Kasteleijn-Nolst Trenité, Dorothée, de Haan, Gerrit-Jan, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Steinhoff, Bernhard J., Kleefu-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Elger, Christian E., Muhle, Hiltrud, von Spiczak, Sarah, Ostertag, Philipp, Helbig, Ingo, Stephani, Ulrich, Møller, Rikke S., Hjalgrim, Helle, Dibbens, Leanne M., Bellows, Susannah, Oliver, Karen, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Guipponi, Michel, Malafosse, Alain, Thomas, Pierre, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Guerrero, Rosa, Serratosa, Jose M., Reif, Philipp S., Rosenow, Felix, Mörzinger, Martina, Feucht, Martha, Zimprich, Fritz, Kapser, Claudia, Schankin, Christoph J., Suls, Arvid, Smets, Katrin, De Jonghe, Peter, Jordanova, Albena, Caglayan, Hande, Yapici, Zuhal, Yalcin, Destina A., Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Gieger, Christian, Wichmann, Heinz-Erich, Balschun, Tobias, Ellinghaus, David, Franke, Andre, Meesters, Christian, Becker, Tim, Wienker, Thomas F., Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Leber, Markus, Pauck, Steffen M., Trucks, Holger, Toliat, Mohammad R., Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., and Sander, Thomas
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- 2012
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168. Acute effects of epigallocatechin gallate from green tea on oxidation and tissue incorporation of dietary lipids in mice fed a high-fat diet
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Friedrich, M, Petzke, K J, Raederstorff, D, Wolfram, S, and Klaus, S
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- 2012
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169. Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies
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Leu, Costin, de Kovel, Carolien G.F., Zara, Federico, Striano, Pasquale, Pezzella, Marianna, Robbiano, Angela, Bianchi, Amedeo, Bisulli, Francesca, Coppola, Antonietta, Giallonardo, Anna Teresa, Beccaria, Francesca, Trenité, Dorothée Kasteleijn-Nolst, Lindhout, Dick, Gaus, Verena, Schmitz, Bettina, Janz, Dieter, Weber, Yvonne G., Becker, Felicitas, Lerche, Holger, Kleefu-Lie, Ailing A., Hallman, Kerstin, Kunz, Wolfram S., Elger, Christian E., Muhle, Hiltrud, Stephani, Ulrich, Mller, Rikke S., Hjalgrim, Helle, Mullen, Saul, Scheffer, Ingrid E., Berkovic, Samuel F., Everett, Kate V., Gardiner, Mark R., Marini, Carla, Guerrini, Renzo, Lehesjoki, Anna-Elina, Siren, Auli, Nabbout, Rima, Baulac, Stephanie, Leguern, Eric, Serratosa, Jose M., Rosenow, Felix, Feucht, Martha, Unterberger, Iris, Covanis, Athanasios, Suls, Arvid, Weckhuysen, Sarah, Kaneva, Radka, Caglayan, Hande, Turkdogan, Dilsad, Baykan, Betul, Bebek, Nerses, Ozbek, Ugur, Hempelmann, Anne, Schulz, Herbert, Rüschendorf, Franz, Trucks, Holger, Nürnberg, Peter, Avanzini, Giuliano, Koeleman, Bobby P.C., and Sander, Thomas
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- 2012
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170. Retinoencephalopathy with occipital lobe epilepsy in an OPA-1 mutation carrier
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Nass, Robert Daniel, Hansen, Niels, Quesada, Carlos, Rüber, Theodor, Kornblum, Cornelia, Zsurka, Gábor, Hermann, Philipp, Becker, Albert, Gärtner, Florian, Hattingen, Elke, Block, Wolfgang, Steidl, Eike, Elger, Christian E., Surges, Rainer, and Kunz, Wolfram S.
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- 2019
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171. Heme is required for carbon monoxide activation of mitochondrial BKCa channel
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Rotko, Daria, primary, Bednarczyk, Piotr, additional, Koprowski, Piotr, additional, Kunz, Wolfram S., additional, Szewczyk, Adam, additional, and Kulawiak, Bogusz, additional
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- 2020
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172. Signaling pathways targeting mitochondrial potassium channels
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Rotko, Daria, primary, Kunz, Wolfram S., additional, Szewczyk, Adam, additional, and Kulawiak, Bogusz, additional
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- 2020
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173. Reply to Rutter et al.: The roles of cytosolic and intramitochondrial Ca2+ and the mitochondrial Ca2+-uniporter (MCU) in the stimulation of mammalian oxidative phosphorylation
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Gellerich, Frank N., primary, Szibor, Marten, additional, Gizatullina, Zemfira, additional, Lessmann, Volkmar, additional, Schwarzer, Michael, additional, Doenst, Torsten, additional, Vielhaber, Stefan, additional, and Kunz, Wolfram S., additional
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- 2020
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174. Cytosolic, but not matrix, calcium is essential for adjustment of mitochondrial pyruvate supply
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Szibor, Marten, primary, Gizatullina, Zemfira, additional, Gainutdinov, Timur, additional, Endres, Thomas, additional, Debska-Vielhaber, Grazyna, additional, Kunz, Matthias, additional, Karavasili, Niki, additional, Hallmann, Kerstin, additional, Schreiber, Frank, additional, Bamberger, Alexandra, additional, Schwarzer, Michael, additional, Doenst, Torsten, additional, Heinze, Hans-Jochen, additional, Lessmann, Volkmar, additional, Vielhaber, Stefan, additional, Kunz, Wolfram S., additional, and Gellerich, Frank N., additional
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- 2020
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175. Pharmacoresponse in genetic generalized epilepsy: a genome-wide association study
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Wolking, Stefan, primary, Schulz, Herbert, additional, Nies, Anne T, additional, McCormack, Mark, additional, Schaeffeler, Elke, additional, Auce, Pauls, additional, Avbersek, Andreja, additional, Becker, Felicitas, additional, Klein, Karl M, additional, Krenn, Martin, additional, Møller, Rikke S, additional, Nikanorova, Marina, additional, Weckhuysen, Sarah, additional, Consortium, EpiPGx, additional, Cavalleri, Gianpiero L, additional, Delanty, Norman, additional, Depondt, Chantal, additional, Johnson, Michael R, additional, Koeleman, Bobby PC, additional, Kunz, Wolfram S, additional, Marson, Anthony G, additional, Sander, Josemir W, additional, Sills, Graeme J, additional, Striano, Pasquale, additional, Zara, Federico, additional, Zimprich, Fritz, additional, Weber, Yvonne G, additional, Krause, Roland, additional, Sisodiya, Sanjay, additional, Schwab, Matthias, additional, Sander, Thomas, additional, and Lerche, Holger, additional
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- 2020
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176. Heart failure after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous DES-p.R349P knock-in mice
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Stöckigt, Florian, primary, Eichhorn, Lars, additional, Beiert, Thomas, additional, Knappe, Vincent, additional, Radecke, Tobias, additional, Steinmetz, Martin, additional, Nickenig, Georg, additional, Peeva, Viktoriya, additional, Kudin, Alexei P., additional, Kunz, Wolfram S., additional, Berwanger, Carolin, additional, Kamm, Lisa, additional, Schultheis, Dorothea, additional, Schlötzer-Schrehardt, Ursula, additional, Clemen, Christoph S., additional, Schröder, Rolf, additional, and Schrickel, Jan W., additional
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- 2020
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177. Energy and greenhouse gases life cycle assessment of electric and hydrogen buses: A real-world case study in Bolzano Italy
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Gianluca Grazieschi, Alyona Zubaryeva, and Wolfram Sparber
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Public transport ,Life cycle assessment ,LCA ,Greenhouse gas ,Electric vehicles ,Electrical engineering. Electronics. Nuclear engineering ,TK1-9971 - Abstract
The transportation sector plays an important role in the current effort towards the control of global warming. Against this backdrop, electrification is currently attracting attention as the life cycle environmental performance of different powertrain technologies is critically assessed. In this study, a life cycle analysis of the public transportation buses was performed. The scope of the analysis is to compare the energy and global warming performances of the different powertrain technologies in the city fleet: diesel, full electric and hydrogen buses. Real world monitored data were used in the analysis for the energy consumptions of the buses and to produce hydrogen in Bolzano. Compared to the traditional diesel buses, the electric vehicles showed a 43% reduction of the non-renewable primary energy demand and a 33% of the global warming potential even in the worst consequential scenario considered. The switch to hydrogen buses leads to very different environmental figures: from very positive if it contributes to a further penetration of renewable electricity, to hardly any difference if hydrogen from steam-methane reforming is used, to clearly negative ones (approximately doubling the impacts) if a predominantly fossil electricity mix is used in the electrolysis.
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- 2023
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178. Effect of Whole-body Vibration frequency on muscle tensile state during graded plantar flexor isometric contractions
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Pornpimol Muanjai, Chris Haas, Wolfram Sies, Uwe Mittag, Jochen Zange, Eckhard Schönau, Ibrahim Duran, Sigitas Kamandulis, and Jörn Rittweger
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Whole body vibration ,Frequency ,Shear wave velocity ,Graded isometric contraction ,Plantar flexor muscles ,Sports ,GV557-1198.995 - Abstract
Background: Acute physiological and biomechanical alterations have been reported following whole-body vibration (WBV). Stiffening of muscles has only been anecdotally reported in response to WBV. Accordingly, this study investigated active plantar flexor muscle stiffness in response to a single WBV bout at four mechanical vibration frequencies. Methods: Thirteen healthy adults (37.1 ± 14.4 years old) randomly received WBV in 4 different frequencies (6, 12, 24, and 0 Hz control) for 5 min. Shear wave speed (SWS) in longitudinal and transverse projections, architecture, and electric muscle activity were recorded in the medial gastrocnemius (MG) and soleus (SOL) muscle during graded plantar flexor contraction. Subjective rating of perceived muscle stiffness was assessed via Likert-scale. Results: SWS of the MG at rest was enhanced in response to 5 min of 24 Hz WBV (p = 0.025), while a small reduction in SOL SWS was found during contraction (p = 0.005) in the longitudinal view. Subjective stiffness rating was increased following 12 Hz intervention. After 24 Hz WBV, pennation angle for MG was decreased (p = 0.011) during contraction. As a secondary finding, plantar flexor strength was significantly increased with each visit, which, however, did not affect the study's main outcome because of balanced sequence allocation. Conclusion: SWS effects were solely limited to 24 Hz mechanical vibration and in the longitudinal projection. The observed effects are compatible with an interpretation by post-activation potentiation, warm-up, and force-distribution within the triceps surae muscles following 5 min WBV. The outcome may suggest SWS as a useful tool for assessing acute changes in muscle stiffness.
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- 2023
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179. Sustained Suppression of Gorlin Syndrome-Associated Basal Cell Carcinomas with Vismodegib or Sonidegib: A Case Series
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Raquel Wescott and Wolfram Samlowski
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nevoid basal cell carcinoma syndrome ,sonidegib ,vismodegib ,hedgehog inhibitors ,Gorlin syndrome ,PTCH mutation ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Nevoid basal-cell carcinoma syndrome (Gorlin syndrome) is characterized by numerous cutaneous basal cell carcinomas mediated by mutations in the hedgehog pathway. Vismodegib or sonidegib represent promising treatment options. We identified 10 Gorlin patients who were treated with sonidegib (n = 6) or vismodegib (n = 4) between March 2012 and March 2022. We analyzed the activity, toxicity, and duration of the response to oral hedgehog inhibitors. The number of new tumors that developed prior to treatment or after treatment as well as the time of response and durability of responses were assessed. All patients achieved a complete remission. With a 30.7 ± 48.4-month median follow-up, the drug treatment significantly reduced the number of new basal cell cancers from a mean of 28.3 ± 24.6 prior to treatment to a mean of 1.4 ± 2.0 during treatment (p = 0.0048). The median time to develop a new basal cell cancer was 47.3 months. Three patients eventually developed localized recurrences. After resection, ongoing treatment suppressed the development of additional lesions. One patient developed numerous new drug-resistant basal cell cancers and died of acute leukemia. Six patients required treatment modifications for toxicity. Sustained hedgehog inhibitor treatment can suppress the progression of both new and existing basal cell carcinomas for an extended period. Drug administration schedule adjustments improved tolerance without altering efficacy, potentially contributing to a prolonged response duration.
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- 2023
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180. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study
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Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), 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), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-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)-Université Paris-Saclay-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)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), 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), 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)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.
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0301 basic medicine ,GAMMA-2-SUBUNIT ,[SDV]Life Sciences [q-bio] ,GABRA5 ,Clinical Neurology ,15Q13.3 MICRODELETIONS ,ABSENCE EPILEPSY ,SEQUENCE DATA ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,3124 Neurology and psychiatry ,03 medical and health sciences ,Epilepsy ,0302 clinical medicine ,Genetic variation ,medicine ,EPILEPTIC ENCEPHALOPATHIES ,Exome ,Exome sequencing ,ComputingMilieux_MISCELLANEOUS ,Genetic association ,Genetics ,RISK ,Science & Technology ,FEBRILE SEIZURES ,Neurology & Neurosurgery ,biology ,3112 Neurosciences ,1103 Clinical Sciences ,MOUSE MODEL ,medicine.disease ,ASSOCIATION ANALYSIS ,030104 developmental biology ,DE-NOVO MUTATIONS ,Cohort ,biology.protein ,Neurology (clinical) ,Human medicine ,Neurosciences & Neurology ,1109 Neurosciences ,Life Sciences & Biomedicine ,030217 neurology & neurosurgery ,Cohort study - Abstract
BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).
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- 2018
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181. Analysis of shared heritability in common disorders of the brain
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Brainstorm Consortium, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K, Walters, Raymond K, Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J, Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A, Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H, Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-François, Duron, Emmanuelle, Vardarajan, Badri N, Reitz, Christiane, Goate, Alison M, Huentelman, Matthew J, Kamboh, M Ilyas, Larson, Eric B, Rogaeva, Ekaterina, St George-Hyslop, Peter, Hakonarson, Hakon, Kukull, Walter A, Farrer, Lindsay A, Barnes, Lisa L, Beach, Thomas G, Demirci, F Yesim, Head, Elizabeth, Hulette, Christine M, Jicha, Gregory A, Kauwe, John SK, Kaye, Jeffrey A, Leverenz, James B, Levey, Allan I, Lieberman, Andrew P, Pankratz, Vernon S, Poon, Wayne W, Quinn, Joseph F, Saykin, Andrew J, Schneider, Lon S, Smith, Amanda G, Sonnen, Joshua A, Stern, Robert A, Van Deerlin, Vivianna M, Van Eldik, Linda J, Harold, Denise, Russo, Giancarlo, Rubinsztein, David C, Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C, Hampel, Harald, Owen, Michael J, Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M, Rossor, Martin, Lupton, Michelle K, Hoffmann, Per, Kornhuber, Johannes, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C, Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J, De Jager, Philip L, Geschwind, Daniel H, Riemenschneider, Matthias, Riedel-Heller, Steffi, Rotter, Jerome I, Ransmayr, Gerhard, Hyman, Bradley T, Cruchaga, Carlos, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nicholas, Kurth, Tobias, Ligthart, Lannie, Terwindt, Gisela M, Freilinger, Tobias, Ran, Caroline, Gordon, Scott D, Borck, Guntram, Adams, Hieab HH, Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E, Schürks, Markus, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G, Montgomery, Grant W, Kurki, Mitja I, Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfons, Pozo-Rosich, Patricia, Hansen, Thomas, Werge, Thomas, Kaprio, Jaakko, Metspalu, Andres, Kubisch, Christian, Ferrari, Michel D, Belin, Andrea C, Van Den Maagdenberg, Arn MJM, Zwart, John-Anker, Boomsma, Dorret, Eriksson, Nicholas, Olesen, Jes, Chasman, Daniel I, Nyholt, Dale R, Avbersek, Andreja, Baum, Larry, Berkovic, Samuel, Bradfield, Jonathan, Buono, Russell J, Catarino, Claudia B, Cossette, Patrick, De Jonghe, Peter, Depondt, Chantal, Dlugos, Dennis, Ferraro, Thomas N, French, Jacqueline, Hjalgrim, Helle, Jamnadas-Khoda, Jennifer, Kälviäinen, Reetta, Kunz, Wolfram S, Lerche, Holger, Leu, Costin, Lindhout, Dick, Lo, Warren, Lowenstein, Daniel, McCormack, Mark, Møller, Rikke S, Molloy, Anne, Ng, Ping-Wing, Oliver, Karen, Privitera, Michael, Radtke, Rodney, Ruppert, Ann-Kathrin, Sander, Thomas, Schachter, Steven, Schankin, Christoph, Scheffer, Ingrid, Schoch, Susanne, Sisodiya, Sanjay M, Smith, Philip, Sperling, Michael, Striano, Pasquale, Surges, Rainer, Thomas, G Neil, Visscher, Frank, Whelan, Christopher D, Zara, Federico, Heinzen, Erin L, Marson, Anthony, Becker, Felicitas, Stroink, Hans, Zimprich, Fritz, Gasser, Thomas, Gibbs, Raphael, Heutink, Peter, Martinez, Maria, Morris, Huw R, Sharma, Manu, Ryten, Mina, Mok, Kin Y, Pulit, Sara, Bevan, Steve, Holliday, Elizabeth, Attia, John, Battey, Thomas, Boncoraglio, Giorgio, Thijs, Vincent, Chen, Wei-Min, Mitchell, Braxton, Rothwell, Peter, Sharma, Pankaj, Sudlow, Cathie, Vicente, Astrid, Markus, Hugh, Kourkoulis, Christina, Pera, Joana, Raffeld, Miriam, Silliman, Scott, Boraska Perica, Vesna, Thornton, Laura M, Huckins, Laura M, William Rayner, N, Lewis, Cathryn M, Gratacos, Monica, Rybakowski, Filip, Keski-Rahkonen, Anna, Raevuori, Anu, Hudson, James I, Reichborn-Kjennerud, Ted, Monteleone, Palmiero, Karwautz, Andreas, Mannik, Katrin, Baker, Jessica H, O'Toole, Julie K, Trace, Sara E, Davis, Oliver SP, Helder, Sietske G, Ehrlich, Stefan, Herpertz-Dahlmann, Beate, Danner, Unna N, Van Elburg, Annemarie A, Clementi, Maurizio, Forzan, Monica, Docampo, Elisa, Lissowska, Jolanta, Hauser, Joanna, Tortorella, Alfonso, Maj, Mario, Gonidakis, Fragiskos, Tziouvas, Konstantinos, Papezova, Hana, Yilmaz, Zeynep, Wagner, Gudrun, Cohen-Woods, Sarah, Herms, Stefan, Julià, Antonio, Rabionet, Raquel, Dick, Danielle M, Ripatti, Samuli, Andreassen, Ole A, Espeseth, Thomas, Lundervold, Astri J, Steen, Vidar M, Pinto, Dalila, Scherer, Stephen W, Aschauer, Harald, Schosser, Alexandra, Alfredsson, Lars, Padyukov, Leonid, Halmi, Katherine A, Mitchell, James, Strober, Michael, Bergen, Andrew W, Kaye, Walter, Szatkiewicz, Jin Peng, Cormand, Bru, Ramos-Quiroga, Josep Antoni, Sánchez-Mora, Cristina, Ribasés, Marta, Casas, Miguel, Hervas, Amaia, Arranz, Maria Jesús, Haavik, Jan, Zayats, Tetyana, Johansson, Stefan, Williams, Nigel, Dempfle, Astrid, Rothenberger, Aribert, Kuntsi, Jonna, Oades, Robert D, Banaschewski, Tobias, Franke, Barbara, Buitelaar, Jan K, Arias Vasquez, Alejandro, Doyle, Alysa E, Reif, Andreas, Lesch, Klaus-Peter, Freitag, Christine, Rivero, Olga, Palmason, Haukur, Romanos, Marcel, Langley, Kate, Rietschel, Marcella, Witt, Stephanie H, Dalsgaard, Soeren, Børglum, Anders D, Waldman, Irwin, Wilmot, Beth, Molly, Nikolas, Bau, Claiton HD, Crosbie, Jennifer, Schachar, Russell, Loo, Sandra K, McGough, James J, Grevet, Eugenio H, Medland, Sarah E, Robinson, Elise, Weiss, Lauren A, Bacchelli, Elena, Bailey, Anthony, Bal, Vanessa, Battaglia, Agatino, Betancur, Catalina, Bolton, Patrick, Cantor, Rita, Celestino-Soper, Patrícia, Dawson, Geraldine, De Rubeis, Silvia, Duque, Frederico, Green, Andrew, Klauck, Sabine M, Leboyer, Marion, Levitt, Pat, Maestrini, Elena, Mane, Shrikant, De-Luca, Daniel Moreno, Parr, Jeremy, Regan, Regina, Reichenberg, Abraham, Sandin, Sven, Vorstman, Jacob, Wassink, Thomas, Wijsman, Ellen, Cook, Edwin, Santangelo, Susan, Delorme, Richard, Rogé, Bernadette, Magalhaes, Tiago, Arking, Dan, Schulze, Thomas G, Thompson, Robert C, Strohmaier, Jana, Matthews, Keith, Melle, Ingrid, Morris, Derek, Blackwood, Douglas, McIntosh, Andrew, Bergen, Sarah E, Schalling, Martin, Jamain, Stéphane, Maaser, Anna, Fischer, Sascha B, Reinbold, Céline S, Fullerton, Janice M, Guzman-Parra, José, Mayoral, Fermin, Schofield, Peter R, Cichon, Sven, Mühleisen, Thomas W, Degenhardt, Franziska, Schumacher, Johannes, Bauer, Michael, Mitchell, Philip B, Gershon, Elliot S, Rice, John, Potash, James B, Zandi, Peter P, Craddock, Nick, Ferrier, I Nicol, Alda, Martin, Rouleau, Guy A, Turecki, Gustavo, Ophoff, Roel, Pato, Carlos, Anjorin, Adebayo, Stahl, Eli, Leber, Markus, Czerski, Piotr M, Cruceanu, Cristiana, Jones, Ian R, Posthuma, Danielle, Andlauer, Till FM, Forstner, Andreas J, Streit, Fabian, Baune, Bernhard T, Air, Tracy, Sinnamon, Grant, Wray, Naomi R, MacIntyre, Donald J, Porteous, David, Homuth, Georg, Rivera, Margarita, Grove, Jakob, Middeldorp, Christel M, Hickie, Ian, Pergadia, Michele, Mehta, Divya, Smit, Johannes H, Jansen, Rick, De Geus, Eco, Dunn, Erin, Li, Qingqin S, Nauck, Matthias, Schoevers, Robert A, Beekman, Aartjan Tf, Knowles, James A, Viktorin, Alexander, Arnold, Paul, Barr, Cathy L, Bedoya-Berrio, Gabriel, Bienvenu, O Joseph, Brentani, Helena, Burton, Christie, Camarena, Beatriz, Cappi, Carolina, Cath, Danielle, Cavallini, Maria, Cusi, Daniele, Darrow, Sabrina, Denys, Damiaan, Derks, Eske M, Dietrich, Andrea, Fernandez, Thomas, Figee, Martijn, Freimer, Nelson, Gerber, Gloria, Grados, Marco, Greenberg, Erica, Hanna, Gregory L, Hartmann, Andreas, Hirschtritt, Matthew E, Hoekstra, Pieter J, Huang, Alden, Huyser, Chaim, Illmann, Cornelia, Jenike, Michael, Kuperman, Samuel, Leventhal, Bennett, Lochner, Christine, Lyon, Gholson J, Macciardi, Fabio, Madruga-Garrido, Marcos, Malaty, Irene A, Maras, Athanasios, McGrath, Lauren, Miguel, Eurípedes C, Mir, Pablo, Nestadt, Gerald, Nicolini, Humberto, Okun, Michael S, Pakstis, Andrew, Paschou, Peristera, Piacentini, John, Pittenger, Christopher, Plessen, Kerstin, Ramensky, Vasily, Ramos, Eliana M, Reus, Victor, Richter, Margaret A, Riddle, Mark A, Robertson, Mary M, Roessner, Veit, Rosário, Maria, Samuels, Jack F, Sandor, Paul, Stein, Dan J, Tsetsos, Fotis, Van Nieuwerburgh, Filip, Weatherall, Sarah, Wendland, Jens R, Wolanczyk, Tomasz, Worbe, Yulia, Zai, Gwyneth, Goes, Fernando S, McLaughlin, Nicole, Nestadt, Paul S, Grabe, Hans-Jorgen, Depienne, Christel, Konkashbaev, Anuar, Lanzagorta, Nuria, Valencia-Duarte, Ana, Bramon, Elvira, Buccola, Nancy, Cahn, Wiepke, Cairns, Murray, Chong, Siow A, Cohen, David, Crespo-Facorro, Benedicto, Crowley, James, Davidson, Michael, DeLisi, Lynn, Dinan, Timothy, Donohoe, Gary, Drapeau, Elodie, Duan, Jubao, Haan, Lieuwe, Hougaard, David, Karachanak-Yankova, Sena, Khrunin, Andrey, Klovins, Janis, Kučinskas, Vaidutis, Lee Chee Keong, Jimmy, Limborska, Svetlana, Loughland, Carmel, Lönnqvist, Jouko, Maher, Brion, Mattheisen, Manuel, McDonald, Colm, Murphy, Kieran C, Nenadic, Igor, Van Os, Jim, Pantelis, Christos, Pato, Michele, Petryshen, Tracey, Quested, Digby, Roussos, Panos, Sanders, Alan R, Schall, Ulrich, Schwab, Sibylle G, Sim, Kang, So, Hon-Cheong, Stögmann, Elisabeth, Subramaniam, Mythily, Toncheva, Draga, Waddington, John, Walters, James, Weiser, Mark, Cheng, Wei, Cloninger, Robert, Curtis, David, Gejman, Pablo V, Henskens, Frans, Mattingsdal, Morten, Oh, Sang-Yun, Scott, Rodney, Webb, Bradley, Breen, Gerome, Churchhouse, Claire, Bulik, Cynthia M, Daly, Mark, Dichgans, Martin, Faraone, Stephen V, Guerreiro, Rita, Holmans, Peter, Kendler, Kenneth S, Koeleman, Bobby, Mathews, Carol A, Price, Alkes, Scharf, Jeremiah, Sklar, Pamela, Williams, Julie, Wood, Nicholas W, Cotsapas, Chris, Palotie, Aarno, Smoller, Jordan W, Sullivan, Patrick, Rosand, Jonathan, Corvin, Aiden, Neale, Benjamin M, Schott, Jonathan M, Anney, Richard, Elia, Josephine, Grigoroiu-Serbanescu, Maria, Edenberg, Howard J, Murray, Robin, Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), School of Psychology [Cardiff University], Cardiff University, Institute for Stroke and Dementia Research (ISD), Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), New Jersey Institute of Technology [Newark] (NJIT), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), RIKEN Center for Integrative Medical Sciences [Yokohama] (RIKEN IMS), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Biotechnologie et Microbiologie Appliquée (LBMA), Université Bordeaux Segalen - Bordeaux 2-Institut National de la Recherche Agronomique (INRA), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), 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), Gériatrie générale et aigüe [Paris], AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Columbia University [New York], Dpt of Neuroscience [New York], Icahn School of Medicine at Mount Sinai [New York] (MSSM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Washington [Seattle], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Children’s Hospital of Philadelphia (CHOP ), University of Kentucky (UK), School of medicine, Duke University [Durham], College of medicine, Brigham Young University (BYU), Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Department of Neurology, Emory University [Atlanta, GA], Medical School, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Health sciences center, The University of New Mexico [Albuquerque], Institute for Memory Impairments and Neurological Disorders [Irvine], University of California [Irvine] (UC Irvine), University of California (UC)-University of California (UC), Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Keck School of Medicine [Los Angeles], University of Southern California (USC), University of South Florida [Tampa] (USF), University of Utah School of Medicine [Salt Lake City], Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Perelman School of Medicine, University of Pennsylvania, Dublin City University [Dublin] (DCU), Functional Genomics Center Zurich, Universität Zürich [Zürich] = University of Zurich (UZH)- Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Cambridge Institute for Medical Research (CIMR), University of Cambridge [UK] (CAM), Aristotle University of Thessaloniki, Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Dementia Research Centre [London] (DRC), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), MRC Centre for Neuropsychiatric Genetics and Genomics, Medical Research Council-Cardiff University, MRC Prion Unit [London], Queen's University [Belfast] (QUB), School of Life Sciences, University of Nottingham, UK (UON), Rheinische Friedrich-Wilhelms-Universität Bonn, Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), QIMR Berghofer Medical Research Institute, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), School of Medicine [Dublin], Trinity College Dublin, Department of Medicine, University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), School of Public Health [Boston], Erasmus University Medical Center [Rotterdam] (Erasmus MC), Columbia University Medical Center (CUMC), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), Saarland University [Saarbrücken], Universität Leipzig, School of Medicine [Los Angeles], Johannes Kepler Universität Linz - Johannes Kepler University Linz [Autriche] (JKU), Department of Neurology [Boston], Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], School of Medecine, Washington University in Saint Louis (WUSTL), Oslo University Hospital [Oslo], Institute for Molecular Medicine Finland [Helsinki] (FIMM), Helsinki Institute of Life Science (HiLIFE), Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, 23andMe Inc., Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Biological Psychology [Amsterdam], Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), Universiteit Leiden, University-Hospital Munich-Großhadern [München], Karolinska Institutet [Stockholm], Universität Ulm - Ulm University [Ulm, Allemagne], Faculty of Medicine and Life Sciences [Tampere], University of Tampere [Finland], Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Landspitali National University Hospital of Iceland, VU University Medical Center [Amsterdam], Boston VA Research Institute (BVARI), Department of Physiology, Anatomy and Genetics [Oxford], University of Oxford, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Christian-Albrechts-Universität zu Kiel (CAU), Institute of Clinical Molecular Biology, Kiel University, National Institute for Health and Welfare [Helsinki], Harvard T.H. Chan School of Public Health, Universitat Autònoma de Barcelona (UAB), Vall d'Hebron University Hospital [Barcelona], University of Tartu, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Center for Human and Clinical Genetics, Universiteit Leiden-Universiteit Leiden, University of Copenhagen = Københavns Universitet (UCPH), Institute of Health and Biomedical Innovation (IHBI), Queensland University of Technology [Brisbane] (QUT), Discipline of Psychiatry [Dublin], Trinity College Dublin-Trinity College Dublin, Institute of Neurology [London], The University of Hong Kong (HKU), University of Melbourne, Cooper Medical School of Rowan University [Camden] (CMSRU), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), University of Antwerp (UA), Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), University of Eastern Finland, Universitätsklinikum Bonn (UKB), Hertie Institute for Clinical Brain Research [Tubingen], University of Tübingen, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, University Medical Center [Utrecht], Ohio State University [Columbus] (OSU), University of California [San Francisco] (UC San Francisco), University of California (UC), Royal College of Surgeons in Ireland (RCSI), University of Southern Denmark (SDU), United Christian Hospital [Hong Kong] (UCH), University of Cincinnati (UC), University of Cologne, Inselspital Bern, University of Wales, Jefferson University Hospitals, University of Liverpool, Medizinische Universität Wien = Medical University of Vienna, National Institutes of Health [Bethesda] (NIH), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Institut de Recherche en Santé Digestive (IRSD ), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Lincoln, University of Newcastle [Callaghan, Australia] (UoN), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', University of Virginia, University of Maryland [Baltimore County] (UMBC), University of Maryland System, Royal Holloway [University of London] (RHUL), University of Edinburgh, Universidade de Lisboa = University of Lisbon (ULISBOA), Uniwersytet Jagielloński w Krakowie = Jagiellonian University (UJ), University of Split, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Center for Genomic Regulation (CRG-UPF), CIBER de Epidemiología y Salud Pública (CIBERESP), McLean Hospital [Belmont, Ma.], Norwegian Institute of Public Health [Oslo] (NIPH), Università degli Studi di Salerno = University of Salerno (UNISA), University of Bristol [Bristol], Technische Universität Dresden = Dresden University of Technology (TU Dresden), Rheinisch-Westfälische Technische Hochschule Aachen University (RWTH), Utrecht University [Utrecht], Azienda Ospedaliera di Padova, Université de Liège, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology (MCMCC), Università degli Studi di Perugia = University of Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, National and Kapodistrian University of Athens (NKUA), Charles University [Prague] (CU), SURFACES, Institut de recherches sur la catalyse et l'environnement de Lyon (IRCELYON), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Flinders University [Adelaide, Australia], Virginia Commonwealth University (VCU), University of Oslo (UiO), University of Bergen (UiB), Weill Medical College of Cornell University [New York], University of North Dakota [Grand Forks] (UND), Oregon Research Institute (ORI), University of California [San Diego] (UC San Diego), Universitat de Barcelona (UB), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Hospital Universitario Mutua de Terrassa, School of Computer Science and Communication [Stockholm], Royal Institute of Technology [Stockholm] (KTH ), Jefferson (Philadelphia University + Thomas Jefferson University), University Medical Center Göttingen (UMG), Universität Heidelberg [Heidelberg] = Heidelberg University, Radboud University Medical Center [Nijmegen], Universitätsklinikum Frankfurt, Maastricht University [Maastricht], Institute of Psychological Medicine and Clinical Neurosciences, Aarhus University [Aarhus], University of Iowa [Iowa City], Universidade Federal do Rio Grande do Sul [Porto Alegre] (UFRGS), The Hospital for sick children [Toronto] (SickKids), Hospital de Clínicas de Porto Alegre (HCPA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), University of British Columbia (UBC), IRCCS Fondazione Stella Maris [Pisa], Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Universidade de Coimbra [Coimbra], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Our Lady's Children's Hospital Crumlin (OLCHC), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), 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), Children’s Hospital Los Angeles [Los Angeles], Yale University [New Haven], Brown University, Institute of Neuroscience [Newcastle] (ION), Newcastle University [Newcastle], Department of Medical Epidemiology and Biostatistics (MEB), Division of Medical Genetics [Seattle], University of Illinois [Chicago] (UIC), University of Illinois System, Maine Medical Center Research Institute (MMCRI), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Centre d’Etudes et de Recherches en Psychopathologie et Psychologie de la Santé (CERPPS), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Toulouse Mind & Brain Institut (TMBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Johns Hopkins University School of Medicine [Baltimore], Ludwig Maximilian University [Munich] (LMU), University of Michigan System, Department of Genetic Epidemiology in Psychiatry [Mannhein], Universität Heidelberg [Heidelberg] = Heidelberg University-Central Institute of Mental Health Mannheim, University of Dundee, National University of Ireland [Galway] (NUI Galway), University Hospital Basel [Basel], Neuroscience Research Australia (NeuRA), Forschungszentrum Jülich GmbH | Centre de recherche de Juliers, Helmholtz-Gemeinschaft = Helmholtz Association, UNSW Faculty of Medicine [Sydney], University of New South Wales [Sydney] (UNSW), University of Chicago, Johns Hopkins University (JHU), Johns Hopkins Bloomberg School of Public Health [Baltimore], Dalhousie University [Halifax], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], State University of New York (SUNY), University Hospital of Cologne [Cologne], University of Adelaide, James Cook University (JCU), Institute for Molecular Bioscience, University of Queensland [Brisbane], Greifswald University Hospital, The University of Sydney, University Medical Center Groningen [Groningen] (UMCG), University of Calgary, University Health Network, Universidad de Antioquia = University of Antioquia [Medellín, Colombia], Universidade de São Paulo = University of São Paulo (USP), Ospedale San Raffaele, University of Amsterdam [Amsterdam] (UvA), University of Groningen [Groningen], Yale School of Medicine [New Haven, Connecticut] (YSM), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Cape Town, Cold Spring Harbor Laboratory (CSHL), Universidad de Sevilla / University of Sevilla, University of Florida [Gainesville] (UF), University of Denver, Purdue University [West Lafayette], Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Moscow Institute of Physics and Technology [Moscow] (MIPT), Sunnybrook Health Sciences Centre, Federal Institute of São Paulo (IFSP), Democritus University of Thrace (DUTH), Universiteit Gent = Ghent University (UGENT), Medical University of Warsaw - Poland, Sorbonne Université - Faculté de Médecine - Département d'Enseignement et de Recherche en Médecine Générale, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Vanderbilt University Medical Center [Nashville], Vanderbilt University [Nashville], Institute of Mental Health [Singapore], Universidad de Cantabria [Santander], Tel Aviv University (TAU), University College Cork (UCC), University of Rochester [USA], Statens Serum Institut [Copenhagen], Софийски университет = Sofia University, Russian Academy of Sciences [Moscow] (RAS), Latvian Biomedical Research and Study Centre [Rīga], Vilnius University [Vilnius], Nanyang Technological University [Singapour], Department of Life Sciences, Imperial College London, Jena University Hospital [Jena], Oxford University Hospitals NHS Trust, Schizophrenia Research Institute [Sydney], Faculty of Science, Medicine and Health [Wollongong], University of Wollongong [Australia], City University of Hong Kong [Hong Kong] (CUHK), Lawrence Berkeley National Laboratory [Berkeley] (LBNL), This work was supported by grants 1R01MH10764901 and 5U01MH09443203 from the National Institute of Mental Health, as well as the Orion Farmos Research Foundation (V.A.) and the Fannie and John Hertz Foundation (H.K.F.). Consortium specific funding is detailed in the supplementary materials ('Study-specific acknowledgments')., Brainstorm Consortium, University of Kentucky, University of California [Irvine] (UCI), University of California-University of California, University of Pennsylvania [Philadelphia], Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universität Leipzig [Leipzig], Johannes Kepler University Linz [Linz] (JKU), University of Helsinki-University of Helsinki, University of Helsinki, University of Oxford [Oxford], University of Copenhagen = Københavns Universitet (KU), University of California [San Francisco] (UCSF), University of California, Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of Virginia [Charlottesville], Universidade de Lisboa (ULISBOA), Università degli Studi di Salerno (UNISA), Rheinisch-Westfälische Technische Hochschule Aachen (RWTH), Università degli Studi di Perugia (UNIPG), Università degli studi della Campania 'Luigi Vanvitelli', Universität Heidelberg [Heidelberg], Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg]-Central Institute of Mental Health Mannheim, VU University Amsterdam, Universidade de São Paulo (USP), Yale University School of Medicine, Universidad de Sevilla, Universiteit Gent = Ghent University [Belgium] (UGENT), Service de Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière] (SPEA), Tel Aviv University [Tel Aviv], University of Sofia, Anttila, Verneri, Bulik-Sullivan, Brendan, Finucane, Hilary K., Walters, Raymond K., Bras, Jose, Duncan, Laramie, Escott-Price, Valentina, Falcone, Guido J., Gormley, Padhraig, Malik, Rainer, Patsopoulos, Nikolaos A., Ripke, Stephan, Wei, Zhi, Yu, Dongmei, Lee, Phil H., Turley, Patrick, Grenier-Boley, Benjamin, Chouraki, Vincent, Kamatani, Yoichiro, Berr, Claudine, Letenneur, Luc, Hannequin, Didier, Amouyel, Philippe, Boland, Anne, Deleuze, Jean-Françoi, Duron, Emmanuelle, Vardarajan, Badri N., Reitz, Christiane, Goate, Alison M., Huentelman, Matthew J., Ilyas Kamboh, M., Larson, Eric B., Rogaeva, Ekaterina, George-Hyslop, Peter St, Hakonarson, Hakon, Kukull, Walter A., Farrer, Lindsay A., Barnes, Lisa L., Beach, Thomas G., Yesim Demirci, F., Head, Elizabeth, Hulette, Christine M., Jicha, Gregory A., Kauwe, John S.K., Kaye, Jeffrey A., Leverenz, James B., Levey, Allan I., Lieberman, Andrew P., Pankratz, Vernon S., Poon, Wayne W., Quinn, Joseph F., Saykin, Andrew J., Schneider, Lon S., Smith, Amanda G., Sonnen, Joshua A., Stern, Robert A., Van Deerlin, Vivianna M., Van Eldik, Linda J., Harold, Denise, Russo, Giancarlo, Rubinsztein, David C., Bayer, Anthony, Tsolaki, Magda, Proitsi, Petra, Fox, Nick C., Hampel, Harald, Owen, Michael J., Mead, Simon, Passmore, Peter, Morgan, Kevin, Nöthen, Markus M., Rossor, Martin, Lupton, Michelle K., Hoffmann, Per, Kornhuber, Johanne, Lawlor, Brian, McQuillin, Andrew, Al-Chalabi, Ammar, Bis, Joshua C., Ruiz, Agustin, Boada, Mercè, Seshadri, Sudha, Beiser, Alexa, Rice, Kenneth, Van Der Lee, Sven J., De Jager, Philip L., Geschwind, Daniel H., Riemenschneider, Matthia, Riedel-Heller, Steffi, Rotter, Jerome I., Ransmayr, Gerhard, Hyman, Bradley T., Cruchaga, Carlo, Alegret, Montserrat, Winsvold, Bendik, Palta, Priit, Farh, Kai-How, Cuenca-Leon, Ester, Furlotte, Nichola, Kurth, Tobia, Ligthart, Lannie, Terwindt, Gisela M., Freilinger, Tobia, Ran, Caroline, Gordon, Scott D., Borck, Guntram, Adams, Hieab H.H., Lehtimäki, Terho, Wedenoja, Juho, Buring, Julie E., Schürks, Marku, Hrafnsdottir, Maria, Hottenga, Jouke-Jan, Penninx, Brenda, Artto, Ville, Kaunisto, Mari, Vepsäläinen, Salli, Martin, Nicholas G., Montgomery, Grant W., Kurki, Mitja I., Hämäläinen, Eija, Huang, Hailiang, Huang, Jie, Sandor, Cynthia, Webber, Caleb, Muller-Myhsok, Bertram, Schreiber, Stefan, Salomaa, Veikko, Loehrer, Elizabeth, Göbel, Hartmut, Macaya, Alfon, Pozo-Rosich, Patricia, Hansen, Thoma, Werge, Thoma, Kaprio, Jaakko, Metspalu, Andre, Kubisch, Christian, Ferrari, Michel D., Belin, Andrea C., Van Den Maagdenberg, Arn M. 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Duque, F, Green, A, Klauck, S, Leboyer, M, Levitt, P, Maestrini, E, Mane, S, Moreno-De-Luca, D, Parr, J, Regan, R, Reichenberg, A, Sandin, S, Vorstman, J, Wassink, T, Wijsman, E, Cook, E, Santangelo, S, Delorme, R, Roge, B, Magalhaes, T, Arking, D, Schulze, T, Thompson, R, Strohmaier, J, Matthews, K, Melle, I, Morris, D, Blackwood, D, Mcintosh, A, Bergen, S, Schalling, M, Jamain, S, Maaser, A, Fischer, S, Reinbold, C, Fullerton, J, Guzman-Parra, J, Mayoral, F, Schofield, P, Cichon, S, Mühleisen, T, Degenhardt, F, Schumacher, J, Bauer, M, Mitchell, P, Gershon, E, Rice, J, Potash, J, Zandi, P, Craddock, N, Nicol Ferrier, I, Alda, M, Rouleau, G, Turecki, G, Ophoff, R, Pato, C, Anjorin, A, Stahl, E, Leber, M, Czerski, P, Cruceanu, C, Jones, I, Posthuma, D, Andlauer, T, Forstner, A, Streit, F, Baune, B, Air, T, Sinnamon, G, Wray, N, Macintyre, D, Porteous, D, Homuth, G, Rivera, M, Grove, J, Middeldorp, C, Hickie, I, Pergadia, M, Mehta, D, Smit, J, Jansen, R, De Geus, E, Dunn, E, Li, Q, Nauck, M, Schoevers, R, Beekman, A, Knowles, J, Viktorin, A, Arnold, P, Barr, C, Bedoya-Berrio, G, Joseph Bienvenu, O, Brentani, H, Burton, C, Camarena, B, Cappi, C, Cath, D, Cavallini, M, Cusi, D, Darrow, S, Denys, D, Derks, E, Dietrich, A, Fernandez, T, Figee, M, Freimer, N, Gerber, G, Grados, M, Greenberg, E, Hanna, G, Hartmann, A, Hirschtritt, M, Hoekstra, P, Huang, A, Huyser, C, Illmann, C, Jenike, M, Kuperman, S, Leventhal, B, Lochner, C, Lyon, G, Macciardi, F, Madruga-Garrido, M, Malaty, I, Maras, A, Mcgrath, L, Miguel, E, Mir, P, Nestadt, G, Nicolini, H, Okun, M, Pakstis, A, Paschou, P, Piacentini, J, Pittenger, C, Plessen, K, Ramensky, V, Ramos, E, Reus, V, Richter, M, Riddle, M, Robertson, M, Roessner, V, Rosário, M, Samuels, J, Sandor, P, Stein, D, Tsetsos, F, Van Nieuwerburgh, F, Weatherall, S, Wendland, J, Wolanczyk, T, Worbe, Y, Zai, G, Goes, F, Mclaughlin, N, Nestadt, P, Grabe, H, Depienne, C, Konkashbaev, A, Lanzagorta, N, Valencia-Duarte, A, Bramon, E, Buccola, N, Cahn, W, Cairns, M, Chong, S, Cohen, D, Crespo-Facorro, B, Crowley, J, Davidson, M, Delisi, L, Dinan, T, Donohoe, G, Drapeau, E, Duan, J, Haan, L, Hougaard, D, Karachanak-Yankova, S, Khrunin, A, Klovins, J, Kučinskas, V, Keong, J, Limborska, S, Loughland, C, Lönnqvist, J, Maher, B, Mattheisen, M, Mcdonald, C, Murphy, K, Nenadic, I, Van Os, J, Pantelis, C, Pato, M, Petryshen, T, Quested, D, Roussos, P, Sanders, A, Schall, U, Schwab, S, Sim, K, So, H, Stögmann, E, Subramaniam, M, Toncheva, D, Waddington, J, Walters, J, Weiser, M, Cheng, W, Cloninger, R, Curtis, D, Gejman, P, Henskens, F, Mattingsdal, M, Oh, S, Scott, R, Webb, B, Breen, G, Churchhouse, C, Bulik, C, Daly, M, Dichgans, M, Faraone, S, Guerreiro, R, Holmans, P, Kendler, K, Koeleman, B, Mathews, C, Price, A, Scharf, J, Sklar, P, Williams, J, Wood, N, Cotsapas, C, Palotie, A, Smoller, J, Sullivan, P, Rosand, J, Corvin, A, Neale, B, Kauwe, John S. K., Mcquillin, Andrew, Adams, Hieab H. H., Mccormack, Mark, Bau, Claiton H. D., Mcgough, James J., Mcintosh, Andrew, Andlauer, Till F. M., Macintyre, Donald J., Mcgrath, Lauren, Mclaughlin, Nicole, Delisi, Lynn, Mcdonald, Colm, Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), RIKEN Center for Integrative Medical Science, Neuropsychiatrie : recherche épidémiologique et clinique, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), University of South Florida (USF), University of Zürich [Zürich] (UZH)-Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology in Zürich [Zürich] (ETH Zürich), Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Cardiff University-Medical Research Council, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Johannes Kepler University Linz [linz] (JKU), Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Universitat Autònoma de Barcelona [Barcelona] (UAB), Hôpital Erasme (Bruxelles), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Jagiellonian University [Krakow] (UJ), Technische Universität Dresden (TUD), National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Charles University [Prague], Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), University of Bergen (UIB), University Medicine Goettingen, Università di Bologna [Bologna] (UNIBO), Forschungszentrum Jülich GmbH, UNSW Medicine [Sydney], McGill University, Universidad de Antioquia, University of Florida [Gainesville], Universiteit Gent [Ghent], Service Psychiatrie de l'Enfant et de l'Adolescent [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], University of Wollongong, Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Anttila, Verneri [0000-0002-0073-4675], Finucane, Hilary K [0000-0003-3864-9828], Walters, Raymond K [0000-0001-8422-6530], Duncan, Laramie [0000-0003-1131-661X], Escott-Price, Valentina [0000-0003-1784-5483], Falcone, Guido J [0000-0002-6407-0302], Gormley, Padhraig [0000-0002-8908-6968], Malik, Rainer [0000-0001-9212-2520], Ripke, Stephan [0000-0003-3622-835X], Wei, Zhi [0000-0001-6059-4267], Yu, Dongmei [0000-0001-7901-4365], Lee, Phil H [0000-0003-1770-3100], Breen, Gerome [0000-0003-2053-1792], Bulik, Cynthia M [0000-0001-7772-3264], Daly, Mark [0000-0002-0949-8752], Dichgans, Martin [0000-0002-0654-387X], Faraone, Stephen V [0000-0002-9217-3982], Holmans, Peter [0000-0003-0870-9412], Koeleman, Bobby [0000-0001-7749-182X], Mathews, Carol A [0000-0003-2208-7058], Sklar, Pamela [0000-0001-9715-4943], Williams, Julie [0000-0002-4069-0259], Wood, Nicholas W [0000-0002-9500-3348], Cotsapas, Chris [0000-0002-7772-5910], Smoller, Jordan W [0000-0002-0381-6334], Sullivan, Patrick [0000-0002-6619-873X], Rosand, Jonathan [0000-0002-1014-9138], Corvin, Aiden [0000-0001-6717-4089], Neale, Benjamin M [0000-0003-1513-6077], and Apollo - University of Cambridge Repository
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Etiology ,[SDV]Life Sciences [q-bio] ,MESH: Brain Diseases ,body-mass index ,genetics [Mental Disorders] ,Disorders of the Brain ,Risks factors ,classification [Mental Disorders] ,MESH: Quantitative Trait, Heritable ,MESH: Risk Factors ,Risk Factors ,MESH: Genetic Variation ,alzheimers-disease ,610 Medicine & health ,bipolar disorder ,Brain Diseases ,deficit hyperactivity disorder ,Multidisciplinary ,Mental Disorders ,genetics [Brain Diseases] ,Brain Disease ,Brain ,Genetic Variation ,Genome-Wide Association Study ,Humans ,Phenotype ,Quantitative Trait, Heritable ,Psychiatric Disorders ,anorexia-nervosa ,Mental Disorder ,Psychiatric Genomics ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,long-term survival ,Engineering sciences. Technology ,Human ,General Science & Technology ,population-based twin ,diagnosis [Mental Disorders] ,MESH: Phenotype ,Neurological Disorders ,Quantitative Trait ,MD Multidisciplinary ,MESH: Mental Disorders ,diagnosis [Brain Diseases] ,Heritable ,genetic correlations ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,major depressive disorder ,Risk Factor ,Brain Diseases/classification ,Brain Diseases/diagnosis ,Brain Diseases/genetics ,Mental Disorders/classification ,Mental Disorders/diagnosis ,Mental Disorders/genetics ,classification [Brain Diseases] ,Perturbações do Desenvolvimento Infantil e Saúde Mental ,ddc:320 ,MESH: Genome-Wide Association Study ,genome-wide association ,Brainstorm Consortium ,Genetic Factors ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities’ assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer’s disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important “scaffolding” to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders.
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- 2018
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182. Linear mitochondrial DNA is rapidly degraded by components of the replication machinery
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Michal Minczuk, Viktoriya Peeva, Alexei P. Kudin, Wolfram S. Kunz, Daniel Blei, Pedro Rebelo-Guiomar, Gábor Zsurka, Payam A. Gammage, Sarah Corsi, Maciej J. Szukszto, Janine Altmüller, Christian Becker, Genevieve Trombly, Minczuk, Michal [0000-0001-8242-1420], Zsurka, Gábor [0000-0002-6379-849X], Kunz, Wolfram S [0000-0003-1113-3493], and Apollo - University of Cambridge Repository
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0301 basic medicine ,DNA Replication ,Mitochondrial DNA ,Science ,Recombinant Fusion Proteins ,General Physics and Astronomy ,ENDOG ,Biology ,Mitochondrion ,medicine.disease_cause ,DNA, Mitochondrial ,General Biochemistry, Genetics and Molecular Biology ,Article ,Electron Transport Complex IV ,03 medical and health sciences ,chemistry.chemical_compound ,medicine ,Humans ,DNA Breaks, Double-Stranded ,DNA Cleavage ,lcsh:Science ,Deoxyribonucleases, Type II Site-Specific ,Polymerase ,Gene Editing ,Mutation ,Multidisciplinary ,Base Sequence ,DNA replication ,DNA Helicases ,Helicase ,General Chemistry ,Genetic Therapy ,Cell biology ,DNA Polymerase gamma ,Mitochondria ,030104 developmental biology ,Exodeoxyribonucleases ,HEK293 Cells ,chemistry ,biology.protein ,lcsh:Q ,CRISPR-Cas Systems ,DNA - Abstract
Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5′-3′exonuclease MGME1, elimination of the 3′-5′exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p.D274A mutation, or knockdown of the mitochondrial DNA helicase TWNK leads to severe impediment of mtDNA degradation. We do not observe similar effects when inactivating other known mitochondrial nucleases (EXOG, APEX2, ENDOG, FEN1, DNA2, MRE11, or RBBP8). Our data suggest that rapid degradation of linearized mtDNA is performed by the same machinery that is responsible for mtDNA replication, thus proposing novel roles for the participating enzymes POLG, TWNK, and MGME1., Damaged linearized mtDNA needs to be removed from the cell for mitochondrial genome stability. Here the authors shed light into the identity of the machinery responsible for rapidly degrading linearized DNA, implicating the role of mtDNA replication factors.
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- 2018
183. Permeabilized cell and skinned fiber techniques in studies of mitochondrial function in vitro
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Veksler, Vladimir I., Kuznetsov, Andrei V., Kay, Laurence, Sikk, Peeter, Tiivel, Toomas, Tranqui, Leone, Olivares, Jose, Winkler, Kirstin, Wiedemann, Falk, and Kunz, Wolfram S.
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- 1998
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184. Impaired mitochondrial oxidative phosphorylation in skeletal muscle of the dystrophin-deficient mdx mouse
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Kuznetsov, Andrey V., Winkler, Kirstin, Wiedemann, Falk, von Bossanyi, Peter, Dietzmann, Knut, and Kunz, Wolfram S.
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- 1998
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185. Functional variants in HCN4 and CACNA1H may contribute to genetic generalized epilepsy
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Georgeta Teodorescu, Han-Shen Tae, A. Marie Phillips, Steven Petrou, Holger Lerche, Christopher A. Reid, Kerstin Hallmann, Ailing A. Kleefuss-Lie, Snezana Maljevic, Wolfram S. Kunz, Christian E. Elger, Felicitas Becker, Yvonne G. Weber, and Edward Perez-Reyes
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0301 basic medicine ,Xenopus ,Biology ,DNA sequencing ,03 medical and health sciences ,0302 clinical medicine ,CACNA1H ,medicine ,HCN4 ,T‐type Ca2+ channels ,Generalized epilepsy ,Gene ,Ion channel ,Genetics ,Functional analysis ,Full‐Length Original Research ,Depolarization ,medicine.disease ,biology.organism_classification ,Thalamo‐cortical circuits ,030104 developmental biology ,Neurology ,biology.protein ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
Summary Objective Genetic generalized epilepsy (GGE) encompasses seizure disorders characterized by spike‐and‐wave discharges (SWD) originating within thalamo‐cortical circuits. Hyperpolarization‐activated (HCN) and T‐type Ca2+ channels are key modulators of rhythmic activity in these brain regions. Here, we screened HCN4 and CACNA1H genes for potentially contributory variants and provide their functional analysis. Methods Targeted gene sequencing was performed in 20 unrelated familial cases with different subtypes of GGE, and the results confirmed in 230 ethnically matching controls. Selected variants in CACNA1H and HCN4 were functionally assessed in tsA201 cells and Xenopus laevis oocytes, respectively. Results We discovered a novel CACNA1H (p.G1158S) variant in two affected members of a single family. One of them also carried an HCN4 (p.P1117L) variant inherited from the unaffected mother. In a separate family, an HCN4 variant (p.E153G) was identified in one of several affected members. Voltage‐clamp analysis of CACNA1H (p.G1158S) revealed a small but significant gain‐of‐function, including increased current density and a depolarizing shift of steady‐state inactivation. HCN4 p.P1117L and p.G153E both caused a hyperpolarizing shift in activation and reduced current amplitudes, resulting in a loss‐of‐function. Significance Our results are consistent with a model suggesting cumulative contributions of subtle functional variations in ion channels to seizure susceptibility and GGE.
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- 2017
186. Peripheral nerve atrophy together with higher cerebrospinal fluid progranulin indicate axonal damage in amyotrophic lateral sclerosis
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Reinhard Dengler, Susanne Abdulla, Sonja Körner, Peter J. Nestor, Grazyna Debska-Vielhaber, Katja Kollewe, Wolfram S. Kunz, Stefan Vielhaber, Peter Körtvelyessy, Judith Machts, Siegfried Kropf, Susanne Petri, Frank Schreiber, and Stefanie Schreiber
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Physiology ,Serum albumin ,Blood–brain barrier ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Atrophy ,Cerebrospinal fluid ,Forearm ,Physiology (medical) ,medicine ,Amyotrophic lateral sclerosis ,Ulnar nerve ,biology ,business.industry ,medicine.disease ,Peripheral ,030104 developmental biology ,medicine.anatomical_structure ,biology.protein ,Neurology (clinical) ,business ,Neuroscience ,030217 neurology & neurosurgery - Abstract
Introduction: We aimed to investigate whether sonographic peripheral cross-sectional nerve area (CSA) and progranulin (PGRN), a neuritic growth factor, are related to each other and whether they interact to predict clinical and paraclinical measures in amyotrophic lateral sclerosis (ALS). Methods: We included 55 ALS patients who had forearm median and ulnar nerve CSA, cerebrospinal fluid (CSF) PGRN and serum PGRN measures available. CSF PGRN was normalized against the CSF/serum albumin ratio (Qalb). Using age, sex, height and weight adjusted general linear models we examined CSA x CSF PGRN interaction effects on various measures. Results: There was a medium-effect size inverse relationship between CSA and CSF PGRN, but not between CSA and serum PGRN. Lower CSA values together with higher CSF PGRN levels were linked to smaller motor amplitudes. Discussion: In ALS, the constellation of peripheral nerve atrophy together with higher CSF PGRN levels indicates pronounced axonal damage. This article is protected by copyright. All rights reserved.
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- 2017
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187. Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy
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Noelia Fradejas-Villar, Ann-Kathrin Ruppert, Yvonne G. Weber, Alexander Grote, Herbert Schulz, Christian E. Elger, Gregor Baron, Ulrich Schweizer, Elias S.J. Arnér, Gábor Zsurka, Sandra Seeher, Kevin G. Hampel, Lutz Schomburg, Peter Nürnberg, Alexei P. Kudin, Holger Lerche, Wolfram S. Kunz, Qing Cheng, Holger Thiele, and Thomas Sander
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Adult ,Male ,0301 basic medicine ,Thioredoxin Reductase 1 ,Adolescent ,Mutant ,Biology ,medicine.disease_cause ,Biochemistry ,law.invention ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Western blot ,law ,Generalized seizures ,TXNRD1 ,Physiology (medical) ,Exome Sequencing ,medicine ,Humans ,Genetic Predisposition to Disease ,Child ,Muscle, Skeletal ,Sanger sequencing ,chemistry.chemical_classification ,Mutation ,Epilepsy ,medicine.diagnostic_test ,Homozygote ,Glutathione ,Molecular biology ,Blot ,Oxidative Stress ,030104 developmental biology ,Enzyme ,chemistry ,Oxidative stress ,Child, Preschool ,Recombinant DNA ,symbols ,Epilepsy, Generalized ,Female ,Reactive Oxygen Species ,030217 neurology & neurosurgery - Abstract
Increased oxidative stress has been widely implicated in the pathogenesis in various forms of human epilepsy. Here, we report a homozygous mutation in TXNRD1 (thioredoxin reductase 1) in a family with genetic generalized epilepsy. TXNRD1 is an essential selenium-containing enzyme involved in detoxification of reactive oxygen species (ROS) and redox signaling. The TXNRD1 mutation p.Pro190Leu affecting a highly conserved amino acid residue was identified by whole-exome sequencing of blood DNA from the index patient. The detected mutation and its segregation within the family- all siblings of the index patient were homozygous and the parents heterozygous-were confirmed by Sanger sequencing. TXNRD1 activity was determined in subcellular fractions from a skeletal muscle biopsy and skin fibroblasts of the index patient and the expression levels of the mutated protein were assessed by Se-75 labeling and Western blot analysis. As result of the mutation, the activity of TXNRD1 was reduced in the patient's fibroblasts and skeletal muscle (to 34 +/- 3% and 16 +/- 8% of controls, respectively). In fibroblasts, we detected reduced Se-75-labeling of the enzyme (41 +/- 3% of controls). An in-depth in vitro kinetic analysis of the recombinant mutated TXNRD1 indicated 30-40% lowered k(cat)/Se values. Therefore, a reduced activity of the enzyme in the patient's tissue samples is explained by (i) lower enzyme turnover and (ii) reduced abundance of the mutated enzyme as confirmed by Western blotting and Se-75 labeling. The mutant fibroblasts were also found to be less resistant to a hydrogen peroxide challenge. Our data agree with a potential role of insufficient ROS detoxification for disease manifestation in genetic generalized epilepsy.
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- 2017
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188. Single channel studies of the ATP-regulated potassium channel in brain mitochondria
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Glioma, Katarzyna, Bednarczyk, Piotr, Koszela-Piotrowska, Izabela, Kulawiak, Bogusz, Kudin, Alexei, Kunz, Wolfram S., Dolowy, Krzysztof, and Szewczyk, Adam
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- 2009
189. Characterization of superoxide production sites in isolated rat brain and skeletal muscle mitochondria
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Kudin, Alexey P., Debska-Vielhaber, Grazyna, and Kunz, Wolfram S.
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- 2005
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190. Large Phenotypic Variation of Individuals from a Family with a Novel ASPM Mutation Associated with Microcephaly, Epilepsy, and Behavioral and Cognitive Deficits.
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von Wrede, Randi, Schidlowski, Martin, Huppertz, Hans-Jürgen, Rüber, Theodor, Ivo, Anja, Baumgartner, Tobias, Hallmann, Kerstin, Zsurka, Gábor, Helmstaedter, Christoph, Surges, Rainer, and Kunz, Wolfram S.
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PHENOTYPIC plasticity ,MICROCEPHALY ,EPILEPSY ,GENETIC mutation ,INTELLECTUAL disabilities - Abstract
Here, we report a consanguineous family harboring a novel homozygous frame-shift mutation in ASPM leading to a truncation of the ASPM protein after amino acid position 1830. The phenotype of the patients was associated with microcephaly, epilepsy, and behavioral and cognitive deficits. Despite the obvious genetic similarity, the affected patients show a considerable phenotypic heterogeneity regarding the degree of mental retardation, presence of epilepsy and MRI findings. Interestingly, the degree of mental retardation and the presence of epilepsy correlates well with the severity of abnormalities detected in brain MRI. On the other hand, we detected no evidence for substantial nonsense-mediated ASPM transcript decay in blood samples. This indicates that other factors than ASPM expression levels are relevant for the variability of structural changes in brain morphology seen in patients with primary hereditary microcephaly caused by ASPM mutations. [ABSTRACT FROM AUTHOR]
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- 2022
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191. Clonally Expanded Mitochondrial DNA Mutations in Epileptic Individuals With Mutated DNA Polymerase γ
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Zsurka, Gábor, Baron, Miriam, Stewart, Joanna D., Kornblum, Cornelia, Bös, Monika, Sassen, Robert, Taylor, Robert W., Elger, Christian E., Chinnery, Patrick F., and Kunz, Wolfram S.
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- 2008
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192. Apraxia of lid opening mimicking ptosis in compound heterozygosity for A467T and W748S POLG1 mutations
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Paus, Sebastian, Zsurka, Gabor, Baron, Miriam, Deschauer, Marcus, Bamberg, Christian, Klockgether, Thomas, Kunz, Wolfram S., and Kornblum, Cornelia
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- 2008
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193. Subfield-specific Loss of Hippocampal N-acetyl Aspartate in Temporal Lobe Epilepsy
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Vielhaber, Stefan, Niessen, Heiko G., Debska-Vielhaber, Grazyna, Kudin, Alexei P., Wellmer, Jörg, Kaufmann, Jörn, Schönfeld, Mircea Ariel, Fendrich, Robert, Willker, Wieland, Leibfritz, Dieter, Schramm, Johannes, Elger, Christian E., Heinze, Hans-Jochen, and Kunz, Wolfram S.
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- 2008
194. Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures
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Chandrasekhar Kanduri, Amir Samii, Oliver Dittrich-Breiholz, Caiquan Huang, Florian Wegner, Santhilal Subhash, Susanne Petri, Kiran Kumar Bali, Wolfram S. Kunz, Helmut Bertalanffy, Norman Kalmbach, Souvik Kar, and Torsten Glomb
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Adult ,Male ,Hemangioma, Cavernous, Central Nervous System ,lcsh:Medicine ,RNA-Seq ,Diseases ,Disease ,Computational biology ,Biology ,DNA sequencing ,Chromatin remodeling ,Article ,Transcriptome ,Central Nervous System Neoplasms ,Young Adult ,Humans ,lcsh:Science ,Transcriptomics ,Child ,Gene ,Regulation of gene expression ,Multidisciplinary ,lcsh:R ,Middle Aged ,Long non-coding RNA ,Computational biology and bioinformatics ,Gene Expression Regulation, Neoplastic ,Long non-coding RNAs ,lcsh:Q ,Female ,RNA, Long Noncoding - Abstract
Cerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.
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- 2019
195. Genomic and clinical predictors of lacosamide response in refractory epilepsies
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Heavin, Sinéad B., McCormack, Mark, Wolking, Stefan, Slattery, Lisa, Walley, Nicole, Avbersek, Andreja, Novy, Jan, Sinha, Saurabh R., Radtke, Rod, Doherty, Colin, Auce, Pauls, Craig, John, Johnson, Michael R., Koeleman, Bobby P. C., Krause, Roland, Kunz, Wolfram S., Marson, Anthony G., O'Brien, Terence J., Sander, Josemir W., Sills, Graeme J., Stefansson, Hreinn, Striano, Pasquale, Zara, Federico, EPIGEN Consortium, EpiPGX Consortium, Depondt, Chantal, Sisodiya, Sanjay, Goldstein, David, Lerche, Holger, Cavalleri, Gianpiero L., Delanty, Norman, EPIGEN Consortium, EpiPGX Consortium, Wellcome Trust, Imperial College Healthcare NHS Trust- BRC Funding, Commission of the European Communities, and Medical Research Council (MRC)
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Oncology ,medicine.medical_specialty ,Candidate gene ,lacosamide ,Lacosamide ,Neurology [D14] [Human health sciences] ,Clinical Neurology ,Genome-wide association study ,lcsh:RC346-429 ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,Medicine ,GWAS ,EpiPGX Consortium ,Exome ,lcsh:Neurology. Diseases of the nervous system ,030304 developmental biology ,Genetic association ,pharmacogenomics ,0303 health sciences ,Neurologie [D14] [Sciences de la santé humaine] ,business.industry ,EPIGEN Consortium ,Généralités ,pharmacoresistance ,refractory ,3. Good health ,Neurology ,Pharmacogenomics ,Cohort ,Full‐length Original Research ,Neurology (clinical) ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Objective: Clinical and genetic predictors of response to antiepileptic drugs (AEDs) are largely unknown. We examined predictors of lacosamide response in a real-world clinical setting. Methods: We tested the association of clinical predictors with treatment response using regression modeling in a cohort of people with refractory epilepsy. Genetic assessment for lacosamide response was conducted via genome-wide association studies and exome studies, comprising 281 candidate genes. Results: Most patients (479/483) were treated with LCM in addition to other AEDs. Our results corroborate previous findings that patients with refractory genetic generalized epilepsy (GGE) may respond to treatment with LCM. No clear clinical predictors were identified. We then compared 73 lacosamide responders, defined as those experiencing greater than 75% seizure reduction or seizure freedom, to 495 nonresponders (, SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2019
196. Malignant cardiac phenotype after pressure overload in autosomal-dominant desminopathies: Lessons from heterozygous R349P desmin knock-in mice
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Stöckigt, Florian, Eichhorn, Lars, Beiert, Thomas, Knappe, Vincent, Radecke, Tobias, Steinmetz, Martin, Berwanger, Carolin, Nickenig, Georg, Peeva, Viktoriya, Kudin, Alexei P., Kunz, Wolfram S., Clemen, Christoph S., Schröder, Rolf, and Schrickel, Jan W.
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desminopathie ,R349P desmin knock-in mice ,autosomal-dominant - Published
- 2019
197. Quasi-Mendelian Paternal Inheritance of mitochondrial DNA: A notorious artifact, or anticipated mtDNA behavior?
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Konstantin Khrapko, Zoe Fleischmann, Mark Khrapko, Sofia Annis, Wolfram S. Kunz, Dori C. Woods, Peter J.I. Ellis, Kevin Wasko, and Melissa Franco
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Mitochondrial DNA ,symbols.namesake ,Non-Mendelian inheritance ,Nuclear gene ,Evolutionary biology ,Pseudogene ,Haplotype ,Mendelian inheritance ,symbols ,Inheritance (genetic algorithm) ,Biology ,Paternal Inheritance - Abstract
A recent report by Luo et al (2018) in PNAS (DOI:10.1073/pnas.1810946115) presented evidence of biparental inheritance of mitochondrial DNA. The pattern of inheritance, however, resembled that of a nuclear gene. The authors explained this peculiarity with Mendelian segregation of a faulty gatekeeper gene that permits survival of paternal mtDNA in the oocyte. Three other groups (Vissing, 2019; Lutz-Bonengel and Parson, 2019; Salas et al, 2019), however, posited the observation was an artifact of inheritance of mtDNA nuclear pseudogenes (NUMTs), present in the father’s nuclear genome. We present justification that both interpretations are incorrect, but that the original authors did, in fact, observe biparental inheritance of mtDNA. Our alternative model assumes that because of initially low paternal mtDNA copy number these copies are randomly partitioned into nascent cell lineages. The paternal mtDNA haplotype must have a selective advantage, so ‘seeded’ cells will tend to proceed to fixation of the paternal haplotype in the course of development. We use modeling to emulate the dynamics of paternal genomes and predict their mode of inheritance and distribution in somatic tissue. The resulting offspring is a mosaic of cells that are purely maternal or purely paternal – including in the germline. This mosaicism explains the quasi-Mendelian segregation of the paternal mDNA. Our model is based on known aspects of mtDNA biology and explains all of the experimental observations outlined in Luo et. al., including maternal inheritance of the grand-paternal mtDNA.
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- 2019
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198. Maligner kardialer Phänotyp durch induzierte Widerstandsdruckerhöhung in autosomal-dominanten Desminopathien
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Christoph S. Clemen, Viktoriya Peeva, Rolf Schröder, Vincent Knappe, Carolin Berwanger, T Radecke, Florian Stöckigt, Georg Nickenig, Wolfram S. Kunz, J W Schrickel, Lars Eichhorn, Thomas Beiert, and Martin Steinmetz
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- 2019
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199. Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome
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Victor Shamanskiy, Alina A. Mikhailova, Kristina Ushakova, Alina G. Mikhailova, Sergei Oreshkov, Dmitry Knorre, Evgenii O. Tretiakov, Natalia Ri, Jonathan B. Overdevest, Samuel W. Lukowski, Irina Gostimskaya, Valerian Yurov, Chia-Wei Liou, Tsu-Kung Lin, Wolfram S. Kunz, Alexandre Reymond, Ilya Mazunin, Georgii A. Bazykin, Konstantin Gunbin, Jacques Fellay, Masashi Tanaka, Konstantin Khrapko, and Konstantin Popadin
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Genetics ,Silent mutation ,education.field_of_study ,Somatic cell ,media_common.quotation_subject ,Population ,Longevity ,Biology ,Genome ,Human mitochondrial genetics ,Haplogroup ,Direct repeat ,education ,media_common - Abstract
Aging in postmitotic tissues is associated with clonal expansion of somatic mitochondrial deletions, the origin of which is not well understood. Deletions in mitochondrial DNA (mtDNA) are often flanked by direct nucleotide repeats, but this alone does not fully explain their distribution. Here, we hypothesized that the close proximity of direct repeats on single-stranded DNA might play a role in the formation of deletions. By analyzing human mtDNA deletions in the major arc of mtDNA, which is single-stranded during replication and is characterized by a high number of deletions, we found a non-uniform distribution with a "hot spot" where one deletion breakpoint occurred within the region of 6-9kb and another within 13-16kb of the mtDNA. This distribution was not explained by the presence of direct repeats, suggesting that other factors, such as the spatial proximity of these two regions can be the cause. In silico analyses revealed that the single-stranded major arc may be organized as a large-scale hairpin-like loop with a center close to 11kb and contacting regions between 6-9 kb and 13-16 kb, which would explain the high deletion activity in this contact zone. The direct repeats located within the contact zone, such as the well-known common repeat with a first arm at 8470-8482 bp and a second arm at 13447-13459 bp, are three times more likely to cause deletions compared to direct repeats located outside of the contact zone. An analysis of age- and disease-associated deletions demonstrated that the contact zone plays a crucial role in explaining the age-associated deletions, emphasizing its importance in the rate of healthy aging. Overall, we provide topological insights into the mechanism of age-associated deletion formation in human mtDNA, which could be used to predict somatic deletion burden and maximum lifespan in different human haplogroups and mammalian species.
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- 2019
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200. Mammalian mitochondrial mutational spectrum as a hallmark of cellular and organismal aging
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Jacques Fellay, Alexandre Reymond, Sofia Annis, Masashi Tanaka, Evgenii Tretyakov, Andrei Iurchenko, Alina A. Mikhailova, Irina Gostimskaya, Sergey Nikolaev, Evgeny M. Zdobnov, Melissa Franco, Kristina E. Ushakova, Dmitry A. Knorre, Alina G. Mikhailova, Konstantin Gunbin, Zoe Fleischmann, Vsevolod J. Makeev, Kevin Wasko, Konstantin Popadin, Viktor A. Shamanskiy, Konstantin Khrapko, I. O. Mazunin, Wolfram S. Kunz, Marianna Zazhytska, and V. A. Yurov
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Asynchronous replication ,chemistry.chemical_classification ,Genetics ,Mitochondrial DNA ,Nuclear gene ,media_common.quotation_subject ,Longevity ,Mitochondrion ,Biology ,Oocyte ,chemistry.chemical_compound ,medicine.anatomical_structure ,chemistry ,medicine ,Nucleotide ,DNA ,media_common - Abstract
Mutational spectrum of the mitochondrial genome (mtDNA) does not resemble signatures of any known mutagens and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra may be affected by the oxidative damage which is increasing with cellular and organismal aging. However, the well-documented mutational signature of the oxidative damage, G>T substitutions, is typical only for the nuclear genome while it is extremely rare and age-independent in mtDNA. Thus it is still unclear if there is a mitochondria - specific mutational signature of the oxidative damage. Here, reconstructing mtDNA mutational spectra for human cancers originated from 21 tissues with various cell turnover rate, human oocytes fertilized at different ages, and 424 mammalian species with variable generation length which is a proxy for oocyte age, we observed that the frequency of AH>GHsubstitutions (H- heavy chain notation) is positively correlated with cellular and organismal longevity. Moreover, this mutational bias from AHto GHaffects nucleotide content at the fourfold degenerative synonymous positions leading to a deficit of AHand excess of GH, which is especially pronounced in long-lived mammals. Taking into account additionally, that AH>GHis sensitive to time being single stranded during mtDNA asynchronous replication and A>G is associated with oxidative damage of single-stranded DNA in recent bacterial experiments we propose that AH>GHis a mutational signature of oxidative damage in mtDNA.
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- 2019
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