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medRxiv preprint doi: https://doi.org/10.1101/2020.10.01.20200659; this version posted October 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Large meta-analysis of genome-wide association studies expands knowledge of the genetic etiology of Alzheimer’s disease and highlights potential translational opportunities Céline Bellenguez1,*,#, Fahri Küçükali2,3,4*, Iris Jansen5,6*, Victor Andrade7,8*, Sonia Morenau- Grau9,10,*, Najaf Amin11,12, Benjamin Grenier-Boley1, Anne Boland13, Luca Kleineidam7,8, Peter Holmans14, Pablo Garcia9,10, Rafael Campos Martin7, Adam Naj15,16, Yang Qiong17, Joshua C. Bis18, Vincent Damotte1, Sven Van der Lee5,6,19, Marcos Costa1, Julien Chapuis1, Vilmentas Giedraitis20, María Jesús Bullido10,21, Adolfo López de Munáin10,22, Jordi Pérez- Tur10,23, Pascual Sánchez-Juan10,24, Raquel Sánchez-Valle25, Victoria Álvarez26, Pau Pastor27, Miguel Medina10,28, Jasper Van Dongen2,3,4, Christine Van Broeckhoven2,3,4, Rik Vandenberghe29,30, Sebastiaan Engelborghs31,32, Gael Nicolas33, Florence Pasquier34, Olivier Hanon35, Carole Dufouil36, Claudine Berr37, Stéphanie Debette36, Jean-François Dartigues36, Gianfranco Spalletta38, Benedetta Nacmias39,40, Vincenzo Solfrezzi41, Barbara Borroni42, Lucio Tremolizzo43, Davide Seripa44, Paolo Caffarra45, Antonio Daniele46,47, Daniela Galimberti48,49, Innocenzo Rainero50, Luisa Benussi51, Alesio Squassina52, Patrizia Mecoci53, Lucilla Parnetti54, Carlo Masullo55, Beatrice Arosio56, John Hardy57, Simon Mead58, Kevin Morgan59, Clive Holmes60, Patrick Kehoe61, Bob Woods62, EADB, Charge, ADGC, Jin Sha15,16, Yi Zhao15,63, Chien-Yueh Lee15,63, Pavel P. Kuksa15,63, Kara L. Hamilton-Nelson64, Brian W. Kunkle64,65, William S. Bush66, Eden R. Martin64,65, Li-San Wang15,63, Richard Mayeux67,68, Lindsay A. Farrer69, Jonathan L. Haines66, Margaret A. Pericak-Vance64,65, Ruiqi Wang17, Claudia Satizabal17, Bruce Psaty18, Oscar Lopez18, Florentino Sanchez-Garcia70, Børge G. Nordestgaard71,72, Anne Tybjærg-Hansen72,73, Jesper Qvist Thomassen74, Caroline Graff75,76, Goran Papenberg77, Hilkka Soininen78,79, Miia Kivipelto80,81, Annakaisa Haapasalo82, Tiia Ngandu80,83, Anne Koivisto84,85, teemu kuulasmaa86, Laura Molina Porcel87,88, Johannes Kornhuber89, Oliver Peters90, Anja schneider91, Nikolaos Scarmeas92,93, Martin Dichgans94, Lutz Froelich95, Dan Rujescu96, Janine Diehl-Schmid97, Timo Grimmer97, Matthias Schmid98, Markus M Möthen99, Edna Grünblatt100,101, Julius Popp102, Norbert Scherbaum103, Shima Mehrabian104, Jürgen Deckert105, Dag Aarsland106, Geir Selbæk107, Ingvild Saltvedt108, Srdjan Djurovic109, Henne Holstege5, Yolande A.L. Pijnenburg5, John Van Swieten12, Inez Ramakers110, Aad Van der Lugt111, Jurgen A.H.R Claassen111, Geert Jan Biessels111, Philip Scheltens5, Carmen Antúnez1112, Pablo Mir10,113, Luis Miguel Real114, Jose María García-Alberca115, Gerard Piñol-Ripoll116,117, Guillermo Garcia-Ribas118, Manuel Serrano-Ríos119, Julie Williams14,120, Perminder Sachdev121, Philippe Amouyel1, Karen Mather121, Frank Jessen122,123, Alexandre de Mendonça124, Jakub Hort125,126, Magda Tsolaki127, Ruth Frikke-Schmidt72,73, Jordi Clarimon10,28, Jean-François Deleuze13, Sudha Seshadri128,129, Gerald Schellenberg15,63, Giacomina Rossi130, Ole Andreassen131,132, Martin Ingelsson20, Mikko Hiltunen86, Kristel Sleegers2,3,4, Cornelia Van Duijn11,12,**, Rebecca Sims14,120**, Wiesje M. Van der Flier5,**, Agustin Ruiz9,**, Alfredo Ramirez7,**, Jean-Charles Lambert1,**,# * co-first ** co-last # corresponding author Céline Béllenguez: [email protected] Jean-Charles Lambert: [email protected] 1. Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167-RID-AGE-Facteurs de risque Et déterminants moléculaires des maladies liées au vieillissement, Lille, France. 2. VIB Center for Molecular Neurology, VIB, Antwerp, Belgium. 3. Laboratory of Neurogenetics, Institute Born - Bunge, Antwerp, Belgium 4. Department of Biomedical Sciences, University of Antwerp, B, Antwerp, Belgium 5. Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2020.10.01.20200659; this version posted October 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 6. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University, Amsterdam, the Netherlands 7. Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, University of Cologne, Medical Faculty, 50937 Cologne, Germany. 8. Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, 53127 Bonn, Germany. 9. Research Center and Memory clinic Fundació ACE, Institut Català de Neurociències Aplicades, Universitat Internacional de Catalunya, Barcelona, Spain 10. CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain 11. Nuffield Department of Population Health, University of Oxford, UK 12. Department of Epidemiology, Erasmus Medical Center Rotterdam, the Netherlands. 13. Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, 91057, Evry, France. 14. Division of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK 15. Department of Biostatistics, Epidemiology, and Informatics; University of Pennsylvania Perelman School of Medicine, USA 16. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, USA 17. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA. 18. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA. 19. Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands 20. Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden 21. Centro de Biología Molecular Severo Ochoa (CSIC-UAM (Madrid), Spain 22. Institute Biodonostia, University of Basque Contry (EHU-UPV, San Sebastián), Spain 23. Unitat Mixta de Genètica i Neurologia, Institut d’Investigació Sanitària La Fe (València), Spain. 24. Neurology Service, University Hospital Marqués de Valdecilla (Santander)-IDIVAL-UC), Spain 25. Alzheimer’s disease and other cognitive disorders, Neurology Department, at Hospital Clínic, IDIBAPS (Barcelona), Spain 26. Molecular Genetics Laboratory, at the Hospital Universitario Central de Asturias (Oviedo), Spain 27. Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa (Barcelona), Spain 28. Fundación CIEN (Madrid), Spain 29. Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven, Belgium 30. Neurology Department, University Hospitals Leuven, Leuven, Belgium 31. Department of Neurology and Center for Neurosciences, UZ Brussel and Vrije Universiteit Brussel (VUB), Brussels, Belgium 32. Reference Center for Biological Markers of Dementia (BIODEM), Institute Born-Bunge, University of Antwerp, Antwerp, Belgium 33. Normandie Univ, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and CNR-MAJ, F 76000, Normandy Center for Genomic and Personalized Medicine, Rouen, France 34. Univ Lille, Inserm U1172, CHU, DISTAlz, LiCEND, F-59000 Lille, France 35. APHP, Hôpital Broca, Paris, France 36. Inserm, Bordeaux Population Health Research Center, UMR 1219, Univ. Bordeaux, ISPED, CIC 1401-EC, Univ Bordeaux, F-33000 Bordeaux, France 37. Univ. Montpellier, Inserm U1061, Neuropsychiatry: epidemiological and clinical research, PSNREC, 39 avenue Charles Flahault, BP 34493, 34093, Montpellier cedex 05, France. 38. Laboratory of Neuropsychiatry, IRCCS Santa Lucia Foundation, Rome, Italy 39. Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence Italy 40. IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy 41. "Cesare Frugoni" Internal and Geriatric Medicine and Memory Unit, University of Bari "Aldo Moro" , Bari, Italy. 42. Centre for Neurodegenerative Disorders, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy medRxiv preprint doi: https://doi.org/10.1101/2020.10.01.20200659; this version posted October 4, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . 43. School of Medicine and Surgery, University of Milano-Bicocca and Milan Center for Neuroscience, Italy 44. Complex Structure of Geriatrics, Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. 45. Unit of Neuroscience, DIMEC, University of Parma,
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  • Genome-Wide Profiling of Promoter Methylation in Human

    Genome-Wide Profiling of Promoter Methylation in Human

    Oncogene (2006) 25, 3059–3064 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc TECHNICAL REPORT Genome-wide profiling of promoter methylation in human I Hatada1,2, M Fukasawa1,2, M Kimura1,2, S Morita1,2, K Yamada3, T Yoshikawa3, S Yamanaka4,5, C Endo4, A Sakurada4, M Sato4, T Kondo4, A Horii5, T Ushijima6 and H Sasaki7,8 1Laboratory of Genome Science, Biosignal Genome Resource Center, Department of Molecular and Cellular Biology, Gunma University, Maebashi, Japan; 2PRESTO, Japan Science and Technology Corporation (JST), Kawaguchi, Japan; 3Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan, 4Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan; 5Department of Molecular Pathology, Tohoku University School of Medicine, Sendai, Japan; 6Carcinogenesis Division, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan; 7Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Japan and 8Department of Genetics, School of Life Science, Graduate University for Advanced Studies, Mishima, Japan DNA methylation in the promoter region of a gene is Microarray-based methods of comparing differences in associated with a loss of that gene’s expression and plays DNA methylation in the genome of two samples using an important role in gene silencing. The inactivation of methylation-sensitive restriction enzymes (Yan et al., tumor-suppressor genes by aberrant methylation in the 2001; Hatada et al., 2002) have two problems. The first promoter region is well recognized in carcinogenesis. is that the microarrays contain clones from libraries of However, there has been little study in this area when it CpG islands.
  • YPEL3, a P53-Regulated Gene That Induces Cellular Senescence

    YPEL3, a P53-Regulated Gene That Induces Cellular Senescence

    Published OnlineFirst April 13, 2010; DOI: 10.1158/0008-5472.CAN-09-3219 Molecular and Cellular Pathobiology Cancer Research YPEL3, a p53-Regulated Gene that Induces Cellular Senescence Kevin D. Kelley1, Kelly R. Miller1, Amber Todd1, Amy R. Kelley1, Rebecca Tuttle2, and Steven J. Berberich1 Abstract Cellular senescence, the limited ability of cultured normal cells to divide, can result from cellular damage triggered through oncogene activation (premature senescence) or the loss of telomeres following successive rounds of DNA replication (replicative senescence). Although both processes require a functional p53 signaling pathway, relevant downstream p53 targets have been difficult to identify. Discovery of senescence activators is important because induction of tumor cell senescence may represent a therapeutic approach for the treat- ment of cancer. In microarray studies in which p53 was reactivated in MCF7 cells, we discovered that Yippee- like-3 (YPEL3), a member of a recently discovered family of putative zinc finger motif coding genes consisting of YPEL1-5, is a p53-regulated gene. YPEL3 expression induced by DNA damage leads to p53 recruitment to a cis-acting DNA response element located near the human YPEL3 promoter. Physiologic induction of YPEL3 results in a substantial decrease in cell viability associated with an increase in cellular senescence. Through the use of RNAi and H-ras induction of cellular senescence, we show that YPEL3 activates cellular senescence downstream of p53. Consistent with its growth suppressive activity, YPEL3 gene expression is repressed in ovarian tumor samples. One mechanism of YPEL3 downregulation in ovarian tumor cell lines seems to be hypermethylation of a CpG island upstream of the YPEL3 promoter.