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1. Meta-analysis of genome-wide association studies identifies ancestry-specific associations underlying circulating total tau levels

Author: Chloé Sarnowski, Mohsen Ghanbari, Joshua C. Bis, Mark Logue, Myriam Fornage, Aniket Mishra, Shahzad Ahmad, Alexa S. Beiser, Eric Boerwinkle, Vincent Bouteloup, Vincent Chouraki, L Adrienne Cupples, Vincent Damotte, Charles S. DeCarli, Anita L. DeStefano, Luc Djoussé, Alison E. Fohner, Carol E. Franz, Tiffany F. Kautz, Jean-Charles Lambert, Michael J. Lyons, Thomas H. Mosley, Kenneth J. Mukamal, Matthew P. Pase, Eliana C. Portilla Fernandez, Robert A. Rissman, Claudia L. Satizabal, Ramachandran S. Vasan, Amber Yaqub, Stephanie Debette, Carole Dufouil, Lenore J. Launer, William S. Kremen, William T. Longstreth, M Arfan Ikram, and Sudha Seshadri
Subjects: Biology (General), QH301-705.5
Abstract: A meta-analysis of genome-wide association studies of circulating total-tau levels identifies loci specific to European or African American ancestries, providing further insight to the genetic etiology of neurological diseases.
Published: 2022
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2. Author Correction: Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author: Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, Iris E. Jansen, Nancy L. Pedersen, Najada Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M. Tankard, Joshua C. Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo, Fermin Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Emilio Alarcón-Martín, Sergi Valero, Oscar Sotolongo-Grau, Abbe Ullgren, Adam C. Naj, Afina W. Lemstra, Alba Benaque, Alba Pérez-Cordón, Alberto Benussi, Alberto Rábano, Alessandro Padovani, Alessio Squassina, Alexandre de Mendonça, Alfonso Arias Pastor, Almar A. L. Kok, Alun Meggy, Ana Belén Pastor, Ana Espinosa, Anaïs Corma-Gómez, Angel Martín Montes, Ángela Sanabria, Anita L. DeStefano, Anja Schneider, Annakaisa Haapasalo, Anne Kinhult Ståhlbom, Anne Tybjærg-Hansen, Annette M. Hartmann, Annika Spottke, Arturo Corbatón-Anchuelo, Arvid Rongve, Barbara Borroni, Beatrice Arosio, Benedetta Nacmias, Børge G. Nordestgaard, Brian W. Kunkle, Camille Charbonnier, Carla Abdelnour, Carlo Masullo, Carmen Martínez Rodríguez, Carmen Muñoz-Fernandez, Carole Dufouil, Caroline Graff, Catarina B. Ferreira, Caterina Chillotti, Chandra A. Reynolds, Chiara Fenoglio, Christine Van Broeckhoven, Christopher Clark, Claudia Pisanu, Claudia L. Satizabal, Clive Holmes, Dolores Buiza-Rueda, Dag Aarsland, Dan Rujescu, Daniel Alcolea, Daniela Galimberti, David Wallon, Davide Seripa, Edna Grünblatt, Efthimios Dardiotis, Emrah Düzel, Elio Scarpini, Elisa Conti, Elisa Rubino, Ellen Gelpi, Eloy Rodriguez-Rodriguez, Emmanuelle Duron, Eric Boerwinkle, Evelyn Ferri, Fabrizio Tagliavini, Fahri Küçükali, Florence Pasquier, Florentino Sanchez-Garcia, Francesca Mangialasche, Frank Jessen, Gaël Nicolas, Geir Selbæk, Gemma Ortega, Geneviève Chêne, Georgios Hadjigeorgiou, Giacomina Rossi, Gianfranco Spalletta, Giorgio Giaccone, Giulia Grande, Giuliano Binetti, Goran Papenberg, Harald Hampel, Henri Bailly, Henrik Zetterberg, Hilkka Soininen, Ida K. Karlsson, Ignacio Alvarez, Ildebrando Appollonio, Ina Giegling, Ingmar Skoog, Ingvild Saltvedt, Innocenzo Rainero, Irene Rosas Allende, Jakub Hort, Janine Diehl-Schmid, Jasper Van Dongen, Jean-Sebastien Vidal, Jenni Lehtisalo, Jens Wiltfang, Jesper Qvist Thomassen, Johannes Kornhuber, Jonathan L. Haines, Jonathan Vogelgsang, Juan A. Pineda, Juan Fortea, Julius Popp, Jürgen Deckert, Katharina Buerger, Kevin Morgan, Klaus Fließbach, Kristel Sleegers, Laura Molina-Porcel, Lena Kilander, Leonie Weinhold, Lindsay A. Farrer, Li-San Wang, Luca Kleineidam, Lucia Farotti, Lucilla Parnetti, Lucio Tremolizzo, Lucrezia Hausner, Luisa Benussi, Lutz Froelich, M. Arfan Ikram, M. Candida Deniz-Naranjo, Magda Tsolaki, Maitée Rosende-Roca, Malin Löwenmark, Marc Hulsman, Marco Spallazzi, Margaret A. Pericak-Vance, Margaret Esiri, María Bernal Sánchez-Arjona, Maria Carolina Dalmasso, María Teresa Martínez-Larrad, Marina Arcaro, Markus M. Nöthen, Marta Fernández-Fuertes, Martin Dichgans, Martin Ingelsson, Martin J. Herrmann, Martin Scherer, Martin Vyhnalek, Mary H. Kosmidis, Mary Yannakoulia, Matthias Schmid, Michael Ewers, Michael T. Heneka, Michael Wagner, Michela Scamosci, Miia Kivipelto, Mikko Hiltunen, Miren Zulaica, Montserrat Alegret, Myriam Fornage, Natalia Roberto, Natasja M. van Schoor, Nazib M. Seidu, Nerisa Banaj, Nicola J. Armstrong, Nikolaos Scarmeas, Norbert Scherbaum, Oliver Goldhardt, Oliver Hanon, Oliver Peters, Olivia Anna Skrobot, Olivier Quenez, Ondrej Lerch, Paola Bossù, Paolo Caffarra, Paolo Dionigi Rossi, Paraskevi Sakka, Patrizia Mecocci, Per Hoffmann, Peter A. Holmans, Peter Fischer, Peter Riederer, Qiong Yang, Rachel Marshall, Rajesh N. Kalaria, Richard Mayeux, Rik Vandenberghe, Roberta Cecchetti, Roberta Ghidoni, Ruth Frikke-Schmidt, Sandro Sorbi, Sara Hägg, Sebastiaan Engelborghs, Seppo Helisalmi, Sigrid Botne Sando, Silke Kern, Silvana Archetti, Silvia Boschi, Silvia Fostinelli, Silvia Gil, Silvia Mendoza, Simon Mead, Simona Ciccone, Srdjan Djurovic, Stefanie Heilmann-Heimbach, Steffi Riedel-Heller, Teemu Kuulasmaa, Teodoro del Ser, Thibaud Lebouvier, Thomas Polak, Tiia Ngandu, Timo Grimmer, Valentina Bessi, Valentina Escott-Price, Vilmantas Giedraitis, Vincent Deramecourt, Wolfgang Maier, Xueqiu Jian, Yolande A. L. Pijnenburg, EADB contributors, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, Patrick Gavin Kehoe, Guillermo Garcia-Ribas, Pascual Sánchez-Juan, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo Lopez de Munain, Jose María García-Alberca, María J. Bullido, Victoria Álvarez, Alberto Lleó, Luis M. Real, Pablo Mir, Miguel Medina, Philip Scheltens, Henne Holstege, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Philippe Amouyel, Gerard D. Schellenberg, Julie Williams, Sudha Seshadri, Cornelia M. van Duijn, Karen A. Mather, Raquel Sánchez-Valle, Manuel Serrano-Ríos, Adelina Orellana, Lluís Tárraga, Kaj Blennow, Martijn Huisman, Ole A. Andreassen, Danielle Posthuma, Jordi Clarimón, Mercè Boada, Wiesje M. van der Flier, Alfredo Ramirez, Jean-Charles Lambert, Sven J. van der Lee, and Agustín Ruiz
Subjects: Science
Published: 2023
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3. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Author: Itziar de Rojas, Sonia Moreno-Grau, Niccolo Tesi, Benjamin Grenier-Boley, Victor Andrade, Iris E. Jansen, Nancy L. Pedersen, Najada Stringa, Anna Zettergren, Isabel Hernández, Laura Montrreal, Carmen Antúnez, Anna Antonell, Rick M. Tankard, Joshua C. Bis, Rebecca Sims, Céline Bellenguez, Inés Quintela, Antonio González-Perez, Miguel Calero, Emilio Franco-Macías, Juan Macías, Rafael Blesa, Laura Cervera-Carles, Manuel Menéndez-González, Ana Frank-García, Jose Luís Royo, Fermin Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Diez-Fairen, Carmen Lage, Sebastián García-Madrona, Pablo García-González, Emilio Alarcón-Martín, Sergi Valero, Oscar Sotolongo-Grau, Abbe Ullgren, Adam C. Naj, Afina W. Lemstra, Alba Benaque, Alba Pérez-Cordón, Alberto Benussi, Alberto Rábano, Alessandro Padovani, Alessio Squassina, Alexandre de Mendonça, Alfonso Arias Pastor, Almar A. L. Kok, Alun Meggy, Ana Belén Pastor, Ana Espinosa, Anaïs Corma-Gómez, Angel Martín Montes, Ángela Sanabria, Anita L. DeStefano, Anja Schneider, Annakaisa Haapasalo, Anne Kinhult Ståhlbom, Anne Tybjærg-Hansen, Annette M. Hartmann, Annika Spottke, Arturo Corbatón-Anchuelo, Arvid Rongve, Barbara Borroni, Beatrice Arosio, Benedetta Nacmias, Børge G. Nordestgaard, Brian W. Kunkle, Camille Charbonnier, Carla Abdelnour, Carlo Masullo, Carmen Martínez Rodríguez, Carmen Muñoz-Fernandez, Carole Dufouil, Caroline Graff, Catarina B. Ferreira, Caterina Chillotti, Chandra A. Reynolds, Chiara Fenoglio, Christine Van Broeckhoven, Christopher Clark, Claudia Pisanu, Claudia L. Satizabal, Clive Holmes, Dolores Buiza-Rueda, Dag Aarsland, Dan Rujescu, Daniel Alcolea, Daniela Galimberti, David Wallon, Davide Seripa, Edna Grünblatt, Efthimios Dardiotis, Emrah Düzel, Elio Scarpini, Elisa Conti, Elisa Rubino, Ellen Gelpi, Eloy Rodriguez-Rodriguez, Emmanuelle Duron, Eric Boerwinkle, Evelyn Ferri, Fabrizio Tagliavini, Fahri Küçükali, Florence Pasquier, Florentino Sanchez-Garcia, Francesca Mangialasche, Frank Jessen, Gaël Nicolas, Geir Selbæk, Gemma Ortega, Geneviève Chêne, Georgios Hadjigeorgiou, Giacomina Rossi, Gianfranco Spalletta, Giorgio Giaccone, Giulia Grande, Giuliano Binetti, Goran Papenberg, Harald Hampel, Henri Bailly, Henrik Zetterberg, Hilkka Soininen, Ida K. Karlsson, Ignacio Alvarez, Ildebrando Appollonio, Ina Giegling, Ingmar Skoog, Ingvild Saltvedt, Innocenzo Rainero, Irene Rosas Allende, Jakub Hort, Janine Diehl-Schmid, Jasper Van Dongen, Jean-Sebastien Vidal, Jenni Lehtisalo, Jens Wiltfang, Jesper Qvist Thomassen, Johannes Kornhuber, Jonathan L. Haines, Jonathan Vogelgsang, Juan A. Pineda, Juan Fortea, Julius Popp, Jürgen Deckert, Katharina Buerger, Kevin Morgan, Klaus Fließbach, Kristel Sleegers, Laura Molina-Porcel, Lena Kilander, Leonie Weinhold, Lindsay A. Farrer, Li-San Wang, Luca Kleineidam, Lucia Farotti, Lucilla Parnetti, Lucio Tremolizzo, Lucrezia Hausner, Luisa Benussi, Lutz Froelich, M. Arfan Ikram, M. Candida Deniz-Naranjo, Magda Tsolaki, Maitée Rosende-Roca, Malin Löwenmark, Marc Hulsman, Marco Spallazzi, Margaret A. Pericak-Vance, Margaret Esiri, María Bernal Sánchez-Arjona, Maria Carolina Dalmasso, María Teresa Martínez-Larrad, Marina Arcaro, Markus M. Nöthen, Marta Fernández-Fuertes, Martin Dichgans, Martin Ingelsson, Martin J. Herrmann, Martin Scherer, Martin Vyhnalek, Mary H. Kosmidis, Mary Yannakoulia, Matthias Schmid, Michael Ewers, Michael T. Heneka, Michael Wagner, Michela Scamosci, Miia Kivipelto, Mikko Hiltunen, Miren Zulaica, Montserrat Alegret, Myriam Fornage, Natalia Roberto, Natasja M. van Schoor, Nazib M. Seidu, Nerisa Banaj, Nicola J. Armstrong, Nikolaos Scarmeas, Norbert Scherbaum, Oliver Goldhardt, Oliver Hanon, Oliver Peters, Olivia Anna Skrobot, Olivier Quenez, Ondrej Lerch, Paola Bossù, Paolo Caffarra, Paolo Dionigi Rossi, Paraskevi Sakka, Per Hoffmann, Peter A. Holmans, Peter Fischer, Peter Riederer, Qiong Yang, Rachel Marshall, Rajesh N. Kalaria, Richard Mayeux, Rik Vandenberghe, Roberta Cecchetti, Roberta Ghidoni, Ruth Frikke-Schmidt, Sandro Sorbi, Sara Hägg, Sebastiaan Engelborghs, Seppo Helisalmi, Sigrid Botne Sando, Silke Kern, Silvana Archetti, Silvia Boschi, Silvia Fostinelli, Silvia Gil, Silvia Mendoza, Simon Mead, Simona Ciccone, Srdjan Djurovic, Stefanie Heilmann-Heimbach, Steffi Riedel-Heller, Teemu Kuulasmaa, Teodoro del Ser, Thibaud Lebouvier, Thomas Polak, Tiia Ngandu, Timo Grimmer, Valentina Bessi, Valentina Escott-Price, Vilmantas Giedraitis, Vincent Deramecourt, Wolfgang Maier, Xueqiu Jian, Yolande A. L. Pijnenburg, EADB contributors, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia, Patrick Gavin Kehoe, Guillermo Garcia-Ribas, Pascual Sánchez-Juan, Pau Pastor, Jordi Pérez-Tur, Gerard Piñol-Ripoll, Adolfo Lopez de Munain, Jose María García-Alberca, María J. Bullido, Victoria Álvarez, Alberto Lleó, Luis M. Real, Pablo Mir, Miguel Medina, Philip Scheltens, Henne Holstege, Marta Marquié, María Eugenia Sáez, Ángel Carracedo, Philippe Amouyel, Gerard D. Schellenberg, Julie Williams, Sudha Seshadri, Cornelia M. van Duijn, Karen A. Mather, Raquel Sánchez-Valle, Manuel Serrano-Ríos, Adelina Orellana, Lluís Tárraga, Kaj Blennow, Martijn Huisman, Ole A. Andreassen, Danielle Posthuma, Jordi Clarimón, Mercè Boada, Wiesje M. van der Flier, Alfredo Ramirez, Jean-Charles Lambert, Sven J. van der Lee, and Agustín Ruiz
Subjects: Science
Abstract: Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.
Published: 2021
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4. Large‐scale sequencing studies expand the known genetic architecture of Alzheimer's disease

Author: Diane Xue, William S. Bush, Alan E. Renton, Edoardo A. Marcora, Joshua C. Bis, Brian W. Kunkle, The Alzheimer's Disease Sequencing Project, Eric Boerwinkle, Anita L. DeStefano, Lindsay Farrer, Alison Goate, Richard Mayeux, Margaret Pericak‐Vance, Gerard Schellenberg, Sudha Seshadri, Ellen Wijsman, Jonathan L. Haines, and Elizabeth E. Blue
Subjects: Alzheimer's disease, genetic architecture, genome, networks, pathways, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract Introduction Genes implicated by genome‐wide association studies and family‐based studies of Alzheimer's disease (AD) are largely discordant. We hypothesized that genes identified by sequencing studies like the Alzheimer's Disease Sequencing Project (ADSP) may bridge this gap and highlight shared biological mechanisms. Methods We performed structured literature review of genes prioritized by ADSP studies, genes underlying familial dementias, and genes nominated by genome‐wide association studies. Gene set enrichment analyses of each list identified enriched pathways. Results The genes prioritized by the ADSP, familial dementia studies, and genome‐wide association studies minimally overlapped. Each gene set identified dozens of enriched pathways, several of which were shared (e.g., regulation of amyloid beta clearance). Discussion Alternative study designs provide unique insights into AD genetics. Shared pathways enriched by different genes highlight their relevance to AD pathogenesis, while the patterns of pathway enrichment unique to each gene set provide additional targets for functional studies.
Published: 2021
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5. Integrative methylation score to identify epigenetic modifications associated with lipid changes resulting from fenofibrate treatment in families

Author: Biqi Wang, Anita L. DeStefano, and Honghuang Lin
Subjects: Medicine, Science
Abstract: Abstract Epigenome-wide association studies (EWAS) have traditionally focused on the association test of single epigenetic markers with complex traits. However, it is possible that multiple cytosine-phosphate-guanine (CpG) sites at the same locus could jointly exert their effects on human traits. Therefore, a region-based test that combines multiple markers could be more powerful. We used 2 different region-based tests to investigate the association between changes in DNA methylation and drug response, including the median methylation level test (MMLT) and sequence kernel association test (SKAT). No genes were found to be significantly associated with the drug response (for triglycerides, the false discovery rate ranged from 0.855 to 0.999; for high-density lipoprotein cholesterol, and the false discovery rate ranged from 0.584 to 0.915). Further evidence is needed to explore potential application of gene-level methylation association analysis.
Published: 2018
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6. Network analysis of drug effect on triglyceride-associated DNA methylation

Author: Elise Lim, Hanfei Xu, Peitao Wu, Daniel Posner, Jiayi Wu, Gina M. Peloso, Achilleas N. Pitsillides, Anita L. DeStefano, L. Adrienne Cupples, and Ching-Ti Liu
Subjects: Medicine, Science
Abstract: Abstract Background DNA methylation, an epigenetic modification, can be affected by environmental factors and thus regulate gene expression levels that can lead to alterations of certain phenotypes. Network analysis has been used successfully to discover gene sets that are expressed differently across multiple disease states and suggest possible pathways of disease progression. We applied this framework to compare DNA methylation levels before and after lipid-lowering medication and to identify modules that differ topologically between the two time points, revealing the association between lipid medication and these triglyceride-related methylation sites. Methods We performed quality control using beta-mixture quantile normalization on 463,995 cytosine-phosphate-guanine (CpG) sites and deleted problematic sites, resulting in 423,004 probes. We identified 14,850 probes that were nominally associated with triglycerides prior to treatment and performed weighted gene correlation network analysis (WGCNA) to construct pre- and posttreatment methylation networks of these probes. We then applied both WGCNA module preservation and generalized Hamming distance (GHD) to identify modules with topological differences between the pre- and posttreatment. For modules with structural changes between 2 time points, we performed pathway-enrichment analysis to gain further insight into the biological function of the genes from these modules. Results Six triglyceride-associated modules were identified using pretreatment methylation probes. The same 3 modules were not preserved in posttreatment data using both the module-preservation and the GHD methods. Top-enriched pathways for the 3 differentially methylated modules are sphingolipid signaling pathway, proteoglycans in cancer, and metabolic pathways (p values
Published: 2018
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7. Genetically elevated high‐density lipoprotein cholesterol through the cholesteryl ester transfer protein gene does not associate with risk of Alzheimer's disease

Author: Gina M. Peloso, Sven J. van derLee, International Genomics of Alzheimer's Project (IGAP), R. Sims, S.J. van derLee, A.C. Naj, C. Bellenguez, N. Badarinarayan, J. Jakobsdottir, B.W. Kunkle, A. Boland, R. Raybould, J.C. Bis, E.R. Martin, B. Grenier‐Boley, S. Heilmann‐Heimbach, V. Chouraki, A.B. Kuzma, K. Sleegers, M. Vronskaya, A. Ruiz, R.R. Graham, R. Olaso, P. Hoffmann, M.L. Grove, B.N. Vardarajan, M. Hiltunen, M.M. Nöthen, C.C. White, K.L. Hamilton‐Nelson, J. Epelbaum, W. Maier, S.H. Choi, G.W. Beecham, C. Dulary, S. Herms, A.V. Smith, C.C. Funk, Derbois, A.J. Forstner, S. Ahmad, H. Li, D. Bacq, D. Harold, C.L. Satizabal, O. Valladares, A. Squassina, R. Thomas, J.A. Brody, L. Qu, P. Sánchez‐Juan, T. Morgan, F.J. Wolters, Y. Zhao, F.S. Garcia, N. Denning, M. Fornage, J. Malamon, M.C.D. Naranjo, E. Majounie, T.H. Mosley, B. Dombroski, D. Wallon, M.K. Lupton, J. Dupuis, P. Whitehead, L. Fratiglioni, C. Medway, X. Jian, S. Mukherjee, L. Keller, K. Brown, H. Lin, L.B. Cantwell, F. Panza, B. McGuinness, S. Moreno‐Grau, J.D. Burgess, V. Solfrizzi, P. Proitsi, H.H. Adams, M. Allen, D. Seripa, P. Pastor, L.A. Cupples, N.D. Price, D. Hannequin, A. Frank‐García, D. Levy, P. Chakrabarty, P. Caffarra, I. Giegling, A.S. Beiser, V. Giedraitis, H. Hampel, M.E. Garcia, X. Wang, L. Lannfelt, P. Mecocci, G. Eiriksdottir, P.K. Crane, F. Pasquier, V. Boccardi, I. Henández, R.C. Barber, M. Scherer, L. Tarraga, P.M. Adams, M. Leber, Y. Chen, M.S. Albert, S. Riedel‐Heller, V. Emilsson, D. Beekly, A. Braae, R. Schmidt, D. Blacker, C. Masullo, H. Schmidt, R.S. Doody, G. Spalletta, W.T. Longstreth Jr., T.J. Fairchild, P. Bossù, O.L. Lopez, M.P. Frosch, E. Sacchinelli, B. Ghetti, Q. Yang, R.M. Huebinger, F. Jessen, S. Li, M.I. Kamboh, J. Morris, O. Sotolongo‐Grau, M.J. Katz, C. Corcoran, M. Dunstan, A. Braddel, C. Thomas, A. Meggy, R. Marshall, A. Gerrish, J. Chapman, M. Aguilar, S. Taylor, M. Hill, M.D. Fairén, A. Hodges, B. Vellas, H. Soininen, I. Kloszewska, M. Daniilidou, J. Uphill, Y. Patel, J.T. Hughes, J. Lord, J. Turton, A.M. Hartmann, R. Cecchetti, C. Fenoglio, M. Serpente, M. Arcaro, C. Caltagirone, M.D. Orfei, A. Ciaramella, S. Pichler, M. Mayhaus, W. Gu, A. Lleó, J. Fortea, R. Blesa, I.S. Barber, K. Brookes, C. Cupidi, R.G. Maletta, D. Carrell, S. Sorbi, S. Moebus, M. Urbano, A. Pilotto, J. Kornhuber, P. Bosco, S. Todd, D. Craig, J. Johnston, M. Gill, B. Lawlor, A. Lynch, N.C. Fox, J. Hardy, ARUK Consortium, R.L. Albin, L.G. Apostolova, S.E. Arnold, S. Asthana, C.S. Atwood, C.T. Baldwin, L.L. Barnes, S. Barral, T.G. Beach, J.T. Becker, E.H. Bigio, T.D. Bird, B.F. Boeve, J.D. Bowen, A. Boxer, J.R. Burke, J.M. Burns, J.D. Buxbaum, N.J. Cairns, C. Cao, C.S. Carlson, C.M. Carlsson, R.M. Carney, M.M. Carrasquillo, S.L. Carroll, C.C. Diaz, H.C. Chui, D.G. Clark, D.H. Cribbs, E.A. Crocco, C. DeCarli, M. Dick, R. Duara, D.A. Evans, K.M. Faber, K.B. Fallon, D.W. Fardo, M.R. Farlow, S. Ferris, T.M. Foroud, D.R. Galasko, M. Gearing, D.H. Geschwind, J.R. Gilbert, N.R. Graff‐Radford, R.C. Green, J.H. Growdon, R.L. Hamilton, L.E. Harrell, L.S. Honig, M.J. Huentelman, C.M. Hulette, B.T. Hyman, G.P. Jarvik, E. Abner, L.W. Jin, G. Jun, A. Karydas, J.A. Kaye, R. Kim, N.W. Kowall, J.H. Kramer, F.M. LaFerla, J.J. Lah, J.B. Leverenz, A.I. Levey, G. Li, A.P. Lieberman, K.L. Lunetta, C.G. Lyketsos, D.C. Marson, F. Martiniuk, D.C. Mash, E. Masliah, W.C. McCormick, S.M. McCurry, A.N. McDavid, A.C. McKee, M. Mesulam, B.L. Miller, C.A. Miller, J.W. Miller, J.C. Morris, J.R. Murrell, A.J. Myers, S. O'Bryant, J.M. Olichney, V.S. Pankratz, J.E. Parisi, H.L. Paulson, W. Perry, E. Peskind, A. Pierce, W.W. Poon, H. Potter, J.F. Quinn, A. Raj, M. Raskind, B. Reisberg, C. Reitz, J.M. Ringman, E.D. Roberson, E. Rogaeva, H.J. Rosen, R.N. Rosenberg, M.A. Sager, A.J. Saykin, J.A. Schneider, L.S. Schneider, W.W. Seeley, A.G. Smith, J.A. Sonnen, S. Spina, R.A. Stern, R.H. Swerdlow, R.E. Tanzi, T.A. Thornton‐Wells, J.Q. Trojanowski, J.C. Troncoso, V.M. Van Deerlin, L.J. Van Eldik, H.V. Vinters, J.P. Vonsattel, S. Weintraub, K.A. Welsh‐Bohmer, K.C. Wilhelmsen, J. Williamson, T.S. Wingo, R.L. Woltjer, C.B. Wright, C.E. Yu, L. Yu, F. Garzia, F. Golamaully, G. Septier, S. Engelborghs, R. Vandenberghe, P.P. De Deyn, C.M. Fernadez, Y.A. Benito, H. Thonberg, C. Forsell, L. Lilius, A. Kinhult‐Stählbom, L. Kilander, R. Brundin, L. Concari, S. Helisalmi, A.M. Koivisto, A. Haapasalo, V. Dermecourt, N. Fievet, O. Hanon, C. Dufouil, A. Brice, K. Ritchie, B. Dubois, J.J. Himali, C.D. Keene, J. Tschanz, A.L. Fitzpatrick, W.A. Kukull, M. Norton, T. Aspelund, E.B. Larson, R. Munger, J.I. Rotter, R.B. Lipton, M.J. Bullido, A. Hofman, T.J. Montine, E. Coto, E. Boerwinkle, R.C. Petersen, V. Alvarez, F. Rivadeneira, E.M. Reiman, M. Gallo, C.J. O'Donnell, J.S. Reisch, A.C. Bruni, D.R. Royall, M. Dichgans, M. Sano, D. Galimberti, P. St George‐Hyslop, E. Scarpini, D.W. Tsuang, M. Mancuso, U. Bonuccelli, A.R. Winslow, A. Daniele, C.K. Wu, GERAD/PERADES, CHARGE, ADGC, EADI, O. Peters, B. Nacmias, M. Riemenschneider, R. Heun, C. Brayne, D.C. Rubinsztein, J. Bras, R. Guerreiro, A. Al‐Chalabi, C.E. Shaw, J. Collinge, D. Mann, M. Tsolaki, J. Clarimón, R. Sussams, S. Lovestone, M.C. O'Donovan, M.J. Owen, T.W. Behrens, S. Mead, A.M. Goate, A.G. Uitterlinden, C. Holmes, C. Cruchaga, M. Ingelsson, D.A. Bennett, J. Powell, T.E. Golde, C. Graff, P.L. De Jager, K. Morgan, N. Ertekin‐Taner, O. Combarros, B.M. Psaty, P. Passmore, S.G. Younkin, C. Berr, V. Gudnason, D. Rujescu, D.W. Dickson, J.F. Dartigues, A.L. DeStefano, S. Ortega‐Cubero, H. Hakonarson, D. Campion, M. Boada, J.K. Kauwe, L.A. Farrer, C. Van Broeckhoven, M.A. Ikram, L. Jones, J.L. Haines, C. Tzourio, L.J. Launer, V. Escott‐Price, R. Mayeux, J.F. Deleuze, N. Amin, P.A. Holmans, M.A. Pericak‐Vance, P. Amouyel, C.M. vanDuijn, A. Ramirez, L.S. Wang, J.C. Lambert, S. Seshadri, J. Williams, G.D. Schellenberg, Anita L. Destefano, and Sudha Seshardi
Subjects: Genetics, HDL‐C, Single nucleotide polymorphisms, Instrumental variables, Cholesteryl ester transfer protein, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract: Abstract Introduction There is conflicting evidence whether high‐density lipoprotein cholesterol (HDL‐C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL‐C. We aimed to assess AD risk by genetically predicted HDL‐C. Methods Ten single nucleotide polymorphisms within the CETP locus predicting HDL‐C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR‐Egger. Results Based on 10 single nucleotide polymorphisms distinctly predicting HDL‐C in the CETP locus, we found that HDL‐C was not associated with risk of AD (P > .7). Discussion Our study does not support the role of HDL‐C on risk of AD through HDL‐C altered by CETP. This study does not rule out other mechanisms by which HDL‐C affects risk of AD.
Published: 2018
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8. Postmortem Interval Influences α-Synuclein Expression in Parkinson Disease Brain

Author: Alexandra Dumitriu, Carlee Moser, Tiffany C. Hadzi, Sally L. Williamson, Christopher D. Pacheco, Audrey E. Hendricks, Jeanne C. Latourelle, Jemma B. Wilk, Anita L. DeStefano, and Richard H. Myers
Subjects: Neurology. Diseases of the nervous system, RC346-429
Abstract: Duplications and triplications of the α-synuclein (SNCA) gene increase risk for PD, suggesting increased expression levels of the gene to be associated with increased PD risk. However, past SNCA expression studies in brain tissue report inconsistent results. We examined expression of the full-length SNCA transcript (140 amino acid protein isoform), as well as total SNCA mRNA levels in 165 frontal cortex samples (101 PD, 64 control) using quantitative real-time polymerase chain reaction. Additionally, we evaluated the relationship of eight SNPs in both 5′ and 3′ regions of SNCA with the gene expression levels. The association between postmortem interval (PMI) and SNCA expression was different for PD and control samples: SNCA expression decreased with increasing PMI in cases, while staying relatively constant in controls. For short PMI, SNCA expression was increased in PD relative to control samples, whereas for long PMI, SNCA expression in PD was decreased relative to control samples.
Published: 2012
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9. Evaluation of logistic regression models and effect of covariates for case-control study in RNA-Seq analysis.

Author: Seung Hoan Choi, Adam Labadorf, Richard H. Myers, Kathryn L. Lunetta, Josée Dupuis, and Anita L. DeStefano
Published: 2017
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10. Family history aggregation unit-based tests to detect rare genetic variant associations with application to the Framingham Heart Study

Author: Yanbing Wang, Han Chen, Gina M. Peloso, James B. Meigs, Alexa S. Beiser, Sudha Seshadri, Anita L. DeStefano, and Josée Dupuis
Subjects: Diabetes Mellitus, Type 2, Models, Genetic, Case-Control Studies, Exome Sequencing, Genetics, Genetic Variation, Humans, Exome, Longitudinal Studies, Article, Genetics (clinical)
Abstract: A challenge in standard genetic studies is maintaining good power to detect associations, especially for low prevalent diseases and rare variants. The traditional methods are most powerful when evaluating the association between variants in balanced study designs. Without accounting for family correlation and unbalanced case-control ratio, these analyses could result in inflated type I error. One cost-effective solution to increase statistical power is exploitation of available family history (FH) that contains valuable information about disease heritability. Here, we develop methods to address the aforementioned type I error issues while providing optimal power to analyze aggregates of rare variants by incorporating additional information from FH. With enhanced power in these methods exploiting FH and accounting for relatedness and unbalanced designs, we successfully detect genes with suggestive associations with Alzheimer disease, dementia, and type 2 diabetes by using the exome chip data from the Framingham Heart Study.
Published: 2022
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11. Epigenetic signatures of insulin resistance associated with Alzheimer’s Disease and related traits

Author: Chloé Sarnowski, Marie‐France Hivert, Chunyu Liu, Claudia L Satizabal, Honghuang Lin, Alexa S Beiser, Charles S. DeCarli, Anita L. DeStefano, Josée Dupuis, Alanna C Morrison, and Sudha Seshadri
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2022
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12. Functional Annotations‐Informed Whole Genome Sequence Analysis Identifies Novel Rare Variants for AD in the Alzheimer’s Disease Sequencing Project

Author: Songmi Lee, Bin Shi, Gina M Peloso, Yanbing Wang, Nancy Heard‐Costa, Honghuang Lin, Achilleas N Pitsillides, Chloé Sarnowski, Eric Boerwinkle, Philip L De Jager, Josée Dupuis, Sudha Seshadri, Ellen M Wijsman, Anita L. DeStefano, and Myriam Fornage
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology
Published: 2022
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13. Multiomics integrative analysis identifies APOE allele-specific blood biomarkers associated to Alzheimer’s disease etiopathogenesis

Author: Philippe Amouyel, Pablo Garcia-Gonzalez, Qiong Yang, Joshua C. Bis, Alfredo Ramírez, Luca Kleineidam, Carmen Antúnez-Almagro, Myriam Fornage, Claudia L. Satizabal, Adela Orellana, Rebecca Sims, Juan Marín-Muñoz, Julie Williams, Eric Boerwinkle, Céline Bellenguez, María Eugenia Sáez, Laura Madrid, Rui Xia, Luis Miguel Real, Janina S. Ried, Xueqiu Jian, Shahzad Ahmad, M. Arfan Ikram, Sonia Moreno-Grau, Alzheimer’s Disease Neuroimaging Initiative (Adni), Cornelia M Van Duijn, Sudha Seshadri, Pamela V. Martino Adami, Vincent Damotte, Anita L. DeStefano, Itziar de Rojas, Benjamin Grenier-Boley, Antonio González-Pérez, Agustín Ruiz, Alfredo Cabrera-Socorro, Fuensanta Noguera-Perea, Jean-Charles Lambert, and Epidemiology
Subjects: Apolipoprotein E, Aging, Genome-wide association study, Computational biology, Disease, 03 medical and health sciences, 0302 clinical medicine, medicine, Dementia, ddc:610, Risk factor, Allele, 030304 developmental biology, Genetic association, 0303 health sciences, business.industry, Haplotype, biomarkers, Cell Biology, medicine.disease, 3. Good health, lipids (amino acids, peptides, and proteins), business, Alzheimer’s disease, APOE, 030217 neurology & neurosurgery, Research Paper, integrative analysis
Abstract: Alzheimer’s disease (AD) is the most common form of dementia, currently affecting 35 million people worldwide. Apolipoprotein E (APOE) ε4 allele is the major risk factor for sporadic, late-onset AD (LOAD), which comprises over 95% of AD cases, increasing the risk of AD 4-12 fold. Despite this, the role of APOE in AD pathogenesis is still a mystery. Aiming for a better understanding of APOE-specific effects, the ADAPTED consortium analyzed and integrated publicly available data of multiple OMICS technologies from both plasma and brain stratified by APOE haplotype (APOE2, APOE3 and APOE4). Combining genome-wide association studies (GWAS) with differential mRNA and protein expression analyses and single-nuclei transcriptomics, we identified genes and pathways contributing to AD in both APOE dependent and independent fashion. Interestingly, we characterized a set of biomarkers showing plasma and brain consistent protein profiles and opposite trends in APOE2 and APOE4 AD cases that could constitute screening tools for a disease that lacks specific blood biomarkers. Beside the identification of APOE-specific signatures, our findings advocate that this novel approach, based on the concordance across OMIC layers and tissues, is an effective strategy for overcoming the limitations of often underpowered single-OMICS studies.
Published: 2021
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14. Multi-phenotype analyses of hemostatic traits with cardiovascular events reveal novel genetic associations

Author: Gerard Temprano‐Sagrera, Colleen M. Sitlani, William P. Bone, Miguel Martin‐Bornez, Benjamin F. Voight, Alanna C. Morrison, Scott M. Damrauer, Paul S. de Vries, Nicholas L. Smith, Maria Sabater‐Lleal, Abbas Dehghan, Adam S Heath, Alanna C Morrison, Alex P Reiner, Andrew Johnson, Anne Richmond, Annette Peters, Astrid van Hylckama Vlieg, Barbara McKnight, Bruce M Psaty, Caroline Hayward, Cavin Ward‐Caviness, Christopher O’Donnell, Daniel Chasman, David P Strachan, David A Tregouet, Dennis Mook‐Kanamori, Dipender Gill, Florian Thibord, Folkert W Asselbergs, Frank W.G. Leebeek, Frits R Rosendaal, Gail Davies, Georg Homuth, Gerard Temprano, Harry Campbell, Herman A Taylor, Jan Bressler, Jennifer E Huffman, Jerome I Rotter, Jie Yao, James F Wilson, Joshua C Bis, Julie M Hahn, Karl C Desch, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Lisa R Yanek, Marcus E Kleber, Martina Mueller, Maryam Kavousi, Massimo Mangino, Melissa Liu, Michael R Brown, Matthew P Conomos, Min‐A Jhun, Ming‐Huei Chen, Moniek P.M. de Maat, Nathan Pankratz, Nicholas L Smith, Patricia A Peyser, Paul Elliot, Paul S de Vries, Peng Wei, Philipp S Wild, Pierre E Morange, Pim van der Harst, Qiong Yang, Ngoc‐Quynh Le, Riccardo Marioni, Ruifang Li, Scott M Damrauer, Simon R Cox, Stella Trompet, Stephan B Felix, Uwe Völker, Weihong Tang, Wolfgang Koenig, J. Wouter Jukema, Xiuqing Guo, Sara Lindstrom, Lu Wang, Erin N Smith, William Gordon, Mariza de Andrade, Jennifer A Brody, Jack W Pattee, Jeffrey Haessler, Ben M Brumpton, Daniel I Chasman, Pierre Suchon, Constance Turman, Marine Germain, James MacDonald, Sigrid K Braekkan, Sebastian M Armasu, Rabecca D Jackson, Jonas B Nielsen, Franco Giulianini, Marja K Puurunen, Manal Ibrahim, Susan R Heckbert, Theo K Bammler, Kelly A Frazer, Bryan M McCauley, Kent Taylor, James S Pankow, Alexander P Reiner, Maiken E Gabrielsen, Jean‐François Deleuze, Chris J O’Donnell, Jihye Kim, Peter Kraft, John‐Bjarne Hansen, John A Heit, Charles Kooperberg, Kristian Hveem, Paul M Ridker, Pierre‐Emmanuel Morange, Andrew D Johnson, Christopher Kabrhel, David‐Alexandre Trégouët, Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten‐Jacobs, Anne‐Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Wei‐Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Elizabeth G Holliday, George Howard, Fang‐Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez‐Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin‐Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei‐Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O’Donnell, Sara L Pulit, Kristiina Rannikmäe, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Natalia S Rost, Peter M Rothwell, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil‐Smoller, James G Wilson, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu‐Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean‐François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez‐Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller‐Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba‐Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti‐Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano‐Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres‐Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Christina Jern, Daniel Strbian, Israel Fernandez‐Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, and VU University medical center
Subjects: Hemostasis, genome-wide association study, genetic pleiotropy, Hematology, Polymorphism, Single Nucleotide, Hemostatics, blood coagulation, cardiovascular diseases, Phenotype, Cardiovascular Diseases, Tissue Plasminogen Activator, hemostasis, Humans, Genetic Predisposition to Disease, Factor XI, Genome-Wide Association Study
Abstract: Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85 × 10−9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n = 27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.
Published: 2022
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15. Cardiovascular health, genetic risk, and risk of dementia in the Framingham Heart Study

Author: Vanessa Xanthakis, Anita L. DeStefano, Ramachandran S. Vasan, Matthew P. Pase, Gina M. Peloso, Alexa S. Beiser, Claudia L. Satizabal, and Sudha Seshadri
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Percentile, Offspring, Comorbidity, Article, 03 medical and health sciences, 0302 clinical medicine, Framingham Heart Study, Risk Factors, Internal medicine, Genotype, medicine, Humans, Dementia, Genetic Predisposition to Disease, Longitudinal Studies, Aged, business.industry, Incidence, Hazard ratio, Middle Aged, medicine.disease, Confidence interval, 030104 developmental biology, Cardiovascular Diseases, Cohort, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: ObjectiveTo determine the joint role of ideal cardiovascular health (CVH) and genetic risk on risk of dementia.MethodsWe categorized CVH on the basis of the American Heart Association Ideal CVH Index and genetic risk through a genetic risk score (GRS) of common genetic variants and the APOE ε4 genotype in 1,211 Framingham Heart Study (FHS) offspring cohort participants. We used multivariable Cox proportional hazards regression models to examine the association between CVH, genetic risk, and incident all-cause dementia with up to 10 years of follow-up (mean 8.4 years, 96 incident dementia cases), adjusting for age, sex, and education.ResultsWe observed that a high GRS (>80th percentile) was associated with a 2.6-fold risk of dementia (95% confidence interval [CI] of hazard ratio [HR] 1.23–5.29; p = 0.012) compared with having a low GRS (APOE ε4 allele was associated with a 2.3-fold risk of dementia compared with not carrying an APOE ε4 allele (95% CI of HR 1.49–3.53; p = 0.0002), and having a favorable CVH showed a 0.45-fold lower risk of dementia (95% CI of HR 0.20–1.01; p = 0.0527) compared to having an unfavorable CVH when all 3 components were included in the model. We did not observe an interaction between CVH and GRS (p = 0.99) or APOE ε4 (p = 0.16).ConclusionsWe observed that both genetic risk and CVH contribute additively to dementia risk.
Published: 2020
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16. Evaluation of population stratification adjustment using genome‐wide or exonic variants

Author: Josée Dupuis, Yuning Chen, Anita L. DeStefano, Ching-Ti Liu, and Gina M. Peloso
Subjects: Mixed model, Genotype, Epidemiology, Context (language use), Genome-wide association study, Computational biology, Biology, Population stratification, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Genetic variation, Humans, Computer Simulation, Spurious relationship, Genetic Association Studies, Genetics (clinical), 030304 developmental biology, Genetic association, Principal Component Analysis, 0303 health sciences, Models, Genetic, 030305 genetics & heredity, Confounding, Genetics, Population, Genome-Wide Association Study
Abstract: Population stratification may cause an inflated type-I error and spurious association when assessing the association between genetic variations with an outcome. Many genetic association studies are now using exonic variants, which captures only 1% of the genome, however population stratification adjustments have not been evaluated in the context of exonic variants. We compare the performance of two established approaches: principal components analysis (PCA) and mixed effects models and assess the utility of genome-wide (GW) and exonic variants, by simulation and using a dataset from the Framingham Heart Study. Our results illustrate that although the PCs and genetic relationship matrices (GRM) computed by GW and exonic markers are different, the type-I error rate of association tests for common variants with additive effect appear to be properly controlled in the presence of population stratification. In addition, by considering single nucleotide variants (SNVs) that have different levels of counfounding by population stratification, we also compare the power across multiple association approaches to account for population stratification such as PC-based corrections and mixed effects models. We find that while these 2 methods achieve a similar power for SNVs that have a low or medium level of confounding by population stratification, mixed effects model can reach a higher power for SNVs highly confounded by population stratification.
Published: 2020
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17. RNA-sequencing of human post-mortem hypothalamus and nucleus accumbens identifies expression profiles associated with obesity

Author: Christian Wake, Julie A. Schneider, Thor D. Stein, Joli Bregu, Adam Labadorf, Ann McKee, Philip L. De Jager, David A. Bennett, Sudha Seshadri, Richard H. Myers, and Anita L. DeStefano
Abstract: Obesity, the accumulation of body fat to excess, may cause serious negative health effects, including increased risk of heart disease, type 2 diabetes, stroke and certain cancers. The biology of obesity is complex and not well understood, involving both environmental and genetic factors and affecting metabolic and endocrine mechanisms in tissues of the gut, adipose, and brain. Previous RNA sequencing studies have identified transcripts associated with obesity and body mass index in blood and fat, often using animal models, but RNA sequencing studies in human brain tissue related to obesity have not been previously undertaken. We conducted both large and small RNA sequencing of hypothalamus (207 samples) and nucleus accumbens (276 samples) from individuals defined as consistently obese (124 samples), consistently normal weight as controls (148 samples) or selected without respect to BMI and falling within neither case nor control definition (211 samples), based on longitudinal BMI measures. The samples were provided by three cohort studies with brain donation programs; the Framingham Heart Study (FHS), the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP). For each brain region and large/small RNA sequencing set, differential expression of obesity, BMI, brain region and sex was performed. Analyses were done transcriptome-wide as well as with a priori defined sets of obesity or BMI-associated mRNAs and microRNAs (miRNAs). There are sixteen mRNAs and five microRNAs that are differentially expressed (adjusted p < 0.05) by obesity or BMI in these tissues, several of which were validated with qPCR data. The results include many that are BMI-associated, such as APOBR and CES1, as well as many associated with the immune system and some with addiction, such as the gene sets “cytokine signaling in immune system” and “opioid signaling”. In spite of the relatively large number of samples, our study was likely under-powered to detect other transcripts or miRNA with relevant but smaller effects.
Published: 2022
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18. HaploBuild: an algorithm to construct non-contiguous associated haplotypes in family based genetic studies.

Author: Jason M. Laramie, Jemma B. Wilk, Anita L. DeStefano, and Richard H. Myers
Published: 2007
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19. Exploiting Family History in Aggregation Unit-based Genetic Association Tests

Author: Anita L. DeStefano, Gina M. Peloso, Yanbing Wang, Josée Dupuis, and Han Chen
Subjects: Computer science, Clinical study design, Disease, Computational biology, Biobank, Risk Factors, Case-Control Studies, Hypertension, Genetics, Humans, Dementia, Genetic Testing, Family history, Threshold model, Medical History Taking, Genetics (clinical), Exome sequencing, Type I and type II errors, Genetic association
Abstract: The development of sequencing technology calls for new powerful methods to detect disease associations and lower the cost of sequencing studies. Family history (FH) contains information on disease status of relatives, adding valuable information about the probands’ health problems and risk of diseases. Incorporating data from FH is a cost-effective way to improve statistical evidence in genetic studies, and moreover, overcomes limitations in study designs with insufficient cases or missing genotype information for association analysis. We proposed family history aggregation unit-based test (FHAT) and optimal FHAT (FHAT-O) to exploit available FH for rare variant association analysis. Moreover, we extended liability threshold model of case-control status and FH (LT-FH) method in aggregated unit-based methods and compared that with FHAT and FHAT-O. The computational efficiency and flexibility of the FHAT and FHAT-O were demonstrated through both simulations and applications. We showed that FHAT, FHAT-O and LT-FH method offer reasonable control of the type I error unless case/control ratio is extremely unbalanced, in which case they result in smaller inflation than that observed with conventional methods excluding FH. We also demonstrated that FHAT and FHAT-O are more powerful than LT-FH method and conventional methods in many scenarios. By applying FHAT and FHAT-O to the analysis of all cause dementia and hypertension using the exome sequencing data from the UK Biobank, we showed that our methods can improve significance for known regions. Furthermore, we replicated the previous associations in all cause dementia and hypertension and detected novel regions through the exome-wide analysis.
Published: 2021
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20. Genome-Wide Meta-Analysis of Late-Onset Alzheimer’s Disease Using Rare Variant Imputation in 65,602 Subjects Identifies Novel Rare Variant Locus NCK2: The International Genomics of Alzheimer’s Project (IGAP)

Author: Yuk Yee Leung, Lindsay A. Farrer, Yi Zhao, Amanda B. Kuzma, Jean-Charles Lambert, Alessandra Chesi, Xia R, Haines Jl, Haut J, Anita L. DeStefano, Chouraki, Julie Williams, William S. Bush, Leonenko G, Achilleas N. Pitsillides, John J. Farrell, Richard Mayeux, Fulton-Howard B, Xueqiu Jian, van Duijn C, Edward B. Lee, Sudha Seshadri, Sandra Barral, Li M, Jennifer E. Below, Rebecca Sims, Kara L. Hamilton-Nelson, J. C. Bis, Céline Bellenguez, Struan F.A. Grant, Otto Valladares, B. Grenier-Boley, Schellenberg Gd, Peter Holmans, Margaret A. Pericak-Vance, Comic H, Maria Carolina Dalmasso, Badri N. Vardarajan, Penelope Benchek, Phillips-Cremins Je, Philippe Amouyel, Brian W. Kunkle, Adam C. Naj, Zhang Y, Alfredo Ramirez, Pavel P. Kuksa, Chen H, Jin Sha, Li-San Wang, Lee C, van der Lee Sj, and Josée Dupuis
Subjects: Genetics, 0303 health sciences, TREM2, Haplotype, Genome-wide association study, Locus (genetics), Biology, Minor allele frequency, 03 medical and health sciences, 0302 clinical medicine, Genotype, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology, Genetic association
Abstract: Risk for late-onset Alzheimer’s disease (LOAD) is driven by multiple loci primarily identified by genome-wide association studies, many of which are common variants with minor allele frequencies (MAF)> 0.01. To identify additional common and rare LOAD risk variants, we performed a GWAS on 25,170 LOAD subjects and 41,052 cognitively normal controls in 44 datasets from the International Genomics of Alzheimer’s Project (IGAP). Existing genotype data was imputed using the dense, high-resolution Haplotype Reference Consortium (HRC) r1.1 reference panel. Stage 1 associations of P−5 were meta-analyzed with the European Alzheimer’s Disease Biobank (EADB) (n=20,301 cases; 21,839 controls) (stage 2 combined IGAP and EADB). An expanded meta-analysis was performed using a GWAS of parental AD/dementia history in the UK Biobank (UKBB) (n=35,214 cases; 180,791 controls) (stage 3 combined IGAP, EADB, and UKBB). Common variant (MAF≥0.01) associations were identified for 29 loci in stage 2, including novel genome-wide significant associations at TSPAN14 (P=2.33×10−12), SHARPIN (P=1.56×10−9), and ATF5/SIGLEC11 (P=1.03×10−8), and newly significant associations without using AD proxy cases in MTSS1L/IL34 (P=1.80×10−8), APH1B (P=2.10×10−13), and CLNK (P=2.24×10−10). Rare variant (MAFAPOE and TREM2, and a novel association of a rare variant (rs143080277; MAF=0.0054; P=2.69×10−9) in NCK2, further strengthened with the inclusion of UKBB data in stage 3 (P=7.17×10−13). Single-nucleus sequence data shows that NCK2 is highly expressed in amyloid-responsive microglial cells, suggesting a role in LOAD pathology.
Published: 2021
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21. Genome‐wide meta‐analysis of late‐onset Alzheimer’s disease using rare variant imputation in 65,602 subjects identifies risk loci with roles in memory, neurodevelopment, and cardiometabolic traits: The international genomics of Alzheimer’s project (IGAP)

Author: Brian W. Kunkle, Amanda B. Kuzma, Adam C. Naj, Brian Fulton-Howard, Philippe Amouyel, Julie Williams, Ganna Leonenko, Peter Holmans, Jin Sha, Jonathan L. Haines, Li-San Wang, Benjamin Grenier-Boley, Alfredo Ramirez, Xueqiu Jian, J. C. Bis, Vincent Chouraki, Rebecca Sims, Josée Dupuis, Yi Zhao, Cornelia M. van Duijn, Gerard D. Schellenberg, Achilleas N. Pitsillides, Anita L. DeStefano, Sudha Seshadri, Hata Karamujić-Čomić, Jean-Charles Lambert, Maria Carolina Dalmasso, Lindsay A. Farrer, Margaret A. Pericak-Vance, Sven J. van der Lee, and Rui Xia
Subjects: Genetics, Epidemiology, Health Policy, Genomics, Late onset, Disease, Biology, Omics, Genome, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Meta-analysis, Neurology (clinical), Geriatrics and Gerontology, Imputation (genetics)
Published: 2020
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22. Alzheimer's disease GWAS weighted by multi‐omics and endophenotypes identifies novel risk loci

Author: Sudha Seshadri, Charge Adsp Fus, Yiyi Ma, David A. Bennett, Anita L. DeStefano, Myriam Fornage, Philip L. De Jager, and Badri N. Vardarajan
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Endophenotype, Multi omics, Genome-wide association study, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published: 2020
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23. Assessing whole genome sequencing variation for Alzheimer’s disease in 4707 individuals from the Alzheimer’s Disease Sequencing Project (ADSP)

Author: Margaret A. Pericak-Vance, Eric Boerwinkle, Kara L. Hamilton-Nelson, Chloé Sarnowski, Jairo Ramos, Anita L. DeStefano, Timothy A. Thornton, Honghuang Lin, Ellen M. Wijsman, Eden R. Martin, Brian W. Kunkle, Myriam Fornage, Adam C. Naj, Gina M. Peloso, Gerard D. Schellenberg, Achilleas N. Pitsillides, Yanbing Wang, Richard Mayeux, Sudha Seshadri, Lindsay A. Farrer, Elise M. Lim, Jonathan L. Haines, Josée Dupuis, Li-San Wang, and Gary W. Beecham
Subjects: Whole genome sequencing, Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Variation (linguistics), Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology
Published: 2020
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24. Whole genome sequence association analyses of brain volumes in the TOPMed program

Author: Lisa R. Yanek, Sudha Seshadri, Rasika A. Mathias, Donna K. Arnett, Anita L. DeStefano, Jennifer A. Smith, Paul A. Nyquist, Bruce M. Psaty, Chloé Sarnowski, Claudia L. Satizabal, Charles DeCarli, and Joshua C. Bis
Subjects: Genetics, Whole genome sequencing, Cognitive aging, Epidemiology, Health Policy, Biology, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Endophenotype, medicine, Dementia, Neurology (clinical), Geriatrics and Gerontology, Association (psychology)
Published: 2020
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25. Frequency of familial Alzheimer’s disease gene mutations within the Alzheimer Disease Sequencing Project (ADSP)

Author: Josée Dupuis, Alexandra Scalici, Achilleas N. Pitsillides, Yanbing Wang, Chloé Sarnowski, Anita L. DeStefano, Honghuang Lin, Sudha Seshadri, and Gina M. Peloso
Subjects: Genetics, Epidemiology, business.industry, Health Policy, Gene mutation, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Familial Alzheimer's disease, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease, business
Published: 2020
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26. Genetic analysis of biobank data: Familial history aggregation‐based tests (FHAT) with application to Alzheimer's disease

Author: Gina M. Peloso, Josée Dupuis, Anita L. DeStefano, Han Chen, and Yanbing Wang
Subjects: Genetics, Epidemiology, business.industry, Health Policy, Disease, Genetic analysis, Biobank, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Familial history, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2020
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27. Comparative trans‐ethnic meta‐analysis of whole exome sequencing variation for Alzheimer’s disease (AD) in 18,402 individuals of the Alzheimer’s Disease Sequencing Project (ADSP)

Author: Xueqiu Jian, Anita L. DeStefano, Kara L. Hamilton-Nelson, Farid Rajabli, Myriam Fornage, Jonathan L. Haines, Timothy A. Thornton, Josée Dupuis, Honghuang Lin, Goldie S. Byrd, Ellen M. Wijsman, Sudha Seshadri, Gina M. Peloso, William S. Bush, Eden R. Martin, Richard Mayeux, Margaret A. Pericak-Vance, Claudia L. Satizabal, Brian W. Kunkle, Adam C. Naj, Achilleas N. Pitsillides, Yanbing Wang, and Chloé Sarnowski
Subjects: Genetics, Epidemiology, Health Policy, Ethnic group, Disease, Biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Variation (linguistics), Developmental Neuroscience, Meta-analysis, Neurology (clinical), Geriatrics and Gerontology, Exome sequencing
Published: 2020
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28. Genetic Interaction with Plasma Lipids on Alzheimer’s Disease in the Framingham Heart Study

Author: Gina M. Peloso, Alexa S. Beiser, Sudha Seshadri, and Anita L. DeStefano
Subjects: Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Genotype, Offspring, Single-nucleotide polymorphism, Disease, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Framingham Heart Study, Alzheimer Disease, Risk Factors, Internal medicine, Epidemiology, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, Triglycerides, Cholesterol, business.industry, Incidence, General Neuroscience, General Medicine, Middle Aged, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, chemistry, Cohort, Female, Geriatrics and Gerontology, business, 030217 neurology & neurosurgery, Cohort study
Abstract: Epidemiological and genetic studies have pointed to the role of cholesterol in Alzheimer's disease (AD). We explored the interaction of a genetic risk score (GRS) of AD risk alleles with mid-life plasma lipid levels (LDL-C, HDL-C, and triglycerides) on risk for AD in the Framingham Heart Study (FHS). Mid-life (between the ages of 40-60 years old) lipid levels were obtained from individuals in the FHS Original and Offspring cohorts (157 cases and 2,882 controls) with genetic data and AD status available. Cox proportional hazards regression was performed to test the interaction between mid-life lipid levels and an AD GRS, as well as the individual contributing SNPs, on risk of incident AD adjusting for age, sex, and cohort. We found a significant interaction between a GRS of AD loci and log triglyceride levels on risk of clinical AD (p = 0.006), but no interaction of the GRS with HDL-C (p = 0.458) or LDL-C (p = 0.366). We then tested the interaction between the individual SNPs contributing to the GRS and log triglycerides. We found two SNPs that had interactions with triglycerides on AD risk that reached a p-value < 0.05 (rs11218343 and APOEɛ4). The association between some AD SNPs and risk of AD may be modified by triglyceride levels. Furthermore, sequential testing of a GRS with a set of traits on disease followed by testing individual SNPs for interaction provides a framework for narrowing the associations that need to be tested for interaction analyses. Replication is needed to confirm these findings.
Published: 2018
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29. Whole exome sequencing study identifies novel rare and common Alzheimer’s-Associated variants involved in immune response and transcriptional regulation

Author: Joshua C. Bis, Li-San Wang, Waleed Nasser, Giuseppe Tosto, Jean-Charles Lambert, Gary W. Beecham, Lucinda Fulton, Eric Boerwinkle, Reinhold Schmidt, Kara L. Hamilton-Nelson, Josée Dupuis, Cornelia M. van Duijn, Yuning Chen, Stéphanie Debette, Devanshi Patel, Philippe Amouyel, Gaël Nicolas, Farid Rajabli, Mark J. Daly, Richard Redon, Hilkka Soininen, Anita L. DeStefano, Aki S. Havulinna, Weixin Wang, Margaret A. Pericak-Vance, Chloé Sarnowski, Gerard D. Schellenberg, William S. Bush, Eden R. Martin, John J. Farrell, Richard A. Gibbs, Richard Mayeux, Emmanuelle Génin, Yi Zhao, Kwangsik Nho, Céline Bellenguez, Kari Mattila, Jean-François Deleuze, William J Salerno, Alzheimer’s Disease Sequencing, Brian W. Kunkle, Dominique Campion, Mikko Hiltunen, Richard K. Wilson, Sudha Seshadri, Paul K. Crane, Otto Valladares, Jennifer E. Below, Adam C. Naj, Timothy A. Thornton, Stacey Gabriel, Jan Konrad, Markus Perola, Mark Lathrop, Namrata Gupta, Badri N. Vardarajan, Bruce M. Psaty, Seppo Helisalmi, Jonathan L. Haines, Yiyi Ma, Honghuang Lin, Laura B. Cantwell, Carlos Cruchaga, Alan E. Renton, Terho Lehtimäki, Anne M. Remes, Michael A. Schmidt, Benjamin M. Neale, M. Arfan Ikram, Lindsay A. Farrer, Myriam Fornage, Daniel P. Howrigan, Ellen M. Wijsman, Mitja I. Kurki, Helena Schmidt, Aarno Palotie, Daniel Lancour, Camille Charbonnier, Daniela Witten, Liming Qu, Najaf Amin, Eric S. Lander, Alison Goate, Donna M. Muzny, Kathryn L. Lunetta, Jaakko Kaprio, Edoardo Marcora, Amanda B. Kuzma, Sven J. van der Lee, Shahzad Ahmad, Kim C. Worley, Christophe Tzourio, Benjamin Grenier-Boley, Jean-François Dartigues, L. Adrienne Cupples, Veikko Salomaa, Jaeyoon Chung, Christiane Reitz, Xueqiu Jian, Xiaoling Zhang, Olivier Quenez, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, University of Helsinki, Centre of Excellence in Complex Disease Genetics, Research Programs Unit, Aarno Palotie / Principal Investigator, Genomics of Neurological and Neuropsychiatric Disorders, HUS Helsinki and Uusimaa Hospital District, 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), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), 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), CHU Bordeaux [Bordeaux], Centre National de Recherche en Génomique Humaine (CNRGH), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Génétique, génomique fonctionnelle et biotechnologies (UMR 1078) (GGB), EFS-Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO)-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Epidemiology
Subjects: Male, 0301 basic medicine, DYSBINDIN GENE DTNBP1, Transcription, Genetic, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, SORL1, PROTEIN, Diseases, Genome-wide association study, SUSCEPTIBILITY, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, DISEASE, ABCA7, 0302 clinical medicine, Exome sequencing, Aged, 80 and over, Genetics, RISK, 3. Good health, Psychiatry and Mental health, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, Female, RNA, Long Noncoding, Alzheimer's disease, Immunoglobulin gene, EXPRESSION, Kruppel-Like Transcription Factors, Biology, Article, CODING MUTATIONS, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, Alzheimer Disease, Exome Sequencing, medicine, Humans, GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Genotyping, Aged, Amyloid beta-Peptides, Polymorphism, Genetic, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Immunity, 3112 Neurosciences, Correction, medicine.disease, 030104 developmental biology, Gene Expression Regulation, Haplotypes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Immunoglobulin G, 3111 Biomedicine, 030217 neurology & neurosurgery
Abstract: The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10−7), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10−7), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10−6). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
Published: 2018
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30. A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease

Author: Towfique Raj, Sven J. van der Lee, Julie Williams, Anna A. Pimenova, Benjamin Grenier-Boley, Laura Ibanez, Annette L. Fitzpatrick, Jorge L. Del-Aguila, Benjamin P. Fairfax, Gerard D. Schellenberg, Edoardo Marcora, Anita L. DeStefano, Sarah Bertelsen, Hieab H.H. Adams, Manav Kapoor, Valentina Escott-Price, Carlos Cruchaga, Cornelia M. van Duijn, Alan E. Renton, Richard Mayeux, Céline Bellenguez, Jean-Charles Lambert, Lindsay A. Farrer, Vincent Chouraki, Rebecca Sims, Kuan-lin Huang, Margaret A. Pericak-Vance, Bin Zhang, M. Arfan Ikram, Antonio Fabio Di Narzo, Maria Victoria Fernandez, Philippe Amouyel, Alison Goate, Ingrid B. Borecki, Sheng Chih Jin, Albert V. Smith, Yuetiva Deming, Joshua C. Bis, Jonathan L. Haines, Andrew M. McKenzie, Sudha Seshadri, Lenore J. Launer, John S. K. Kauwe, Oscar Harari, Jake Czajkowski, Ke Hao, John P. Budde, and Epidemiology
Subjects: 0301 basic medicine, Male, Linkage disequilibrium, Myeloid, Locus (genetics), Biology, Polymorphism, Single Nucleotide, Linkage Disequilibrium, Article, 03 medical and health sciences, Mice, Alzheimer Disease, Risk Factors, Proto-Oncogene Proteins, Gene expression, medicine, Animals, Humans, Genetic Predisposition to Disease, Allele, Gene, Alleles, SPI1, General Neuroscience, 030104 developmental biology, medicine.anatomical_structure, Cistrome, Haplotypes, Immunology, Cancer research, Trans-Activators, Female, Genome-Wide Association Study, Transcription Factors
Abstract: A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.
Published: 2017

31. O5‐02‐01: GENOME‐WIDE ASSOCIATION STUDY OF PLASMA TAU LEVELS USING HRC IMPUTATIONS IN THE FRAMINGHAM STUDY

Author: Matthew P. Pase, Chloé Sarnowski, Vincent Chouraki, Anita L. DeStefano, L. Adrienne Cupples, Sudha Seshadri, Ramachandran S. Vasan, Charlie S. DeCarli, Claudia L. Satizabal, and Alexa S. Beiser
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Framingham Heart Study, Developmental Neuroscience, Epidemiology, Health Policy, Genome-wide association study, Neurology (clinical), Computational biology, Geriatrics and Gerontology, Biology
Published: 2019
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32. Analysis of Whole-Exome Sequencing Data for Alzheimer Disease Stratified by APOE Genotype

Author: Gerard D. Schellenberg, Myriam Fornage, Philip L. De Jager, Stéphanie Debette, Lindsay A. Farrer, Eden R. Martin, Richard Mayeux, Brian W. Kunkle, Adam C. Naj, David A. Bennett, Kathryn L. Lunetta, Margaret A. Pericak-Vance, Sudha Seshadri, Jaeyoon Chung, Joshua C. Bis, Gyungah Jun, Yuning Chen, Jean-Charles Lambert, Anita L. DeStefano, Kara L. Hamilton-Nelson, Céline Bellenguez, Gaël Nicolas, Yiyi Ma, Cornelia M. van Duijn, Xiaoling Zhang, Jonathan L. Haines, and Epidemiology
Subjects: Oncology, Apolipoprotein E, medicine.medical_specialty, Genotype imputation, business.industry, Odds ratio, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Genotype, medicine, 030212 general & internal medicine, Neurology (clinical), Allele, Alzheimer's disease, business, 030217 neurology & neurosurgery, Exome sequencing, Genetic association, Original Investigation
Abstract: IMPORTANCE: Previous genome-wide association studies of common variants identified associations for Alzheimer disease (AD) loci evident only among individuals with particular APOE alleles. OBJECTIVE: To identify APOE genotype-dependent associations with infrequent and rare variants using whole-exome sequencing. DESIGN, SETTING, AND PARTICIPANTS: The discovery stage included 10 441 non-Hispanic white participants in the Alzheimer Disease Sequencing Project. Replication was sought in 2 independent, whole-exome sequencing data sets (1766 patients with AD, 2906 without AD [controls]) and a chip-based genotype imputation data set (8728 patients with AD, 9808 controls). Bioinformatics and functional analyses were conducted using clinical, cognitive, neuropathologic, whole-exome sequencing, and gene expression data obtained from a longitudinal cohort sample including 402 patients with AD and 647 controls. Data were analyzed between March 2017 and September 2018. MAIN OUTCOMES AND MEASURES: Score, Firth, and sequence kernel association tests were used to test the association of AD risk with individual variants and genes in subgroups of APOE ε4 carriers and noncarriers. Results with P ≤ 1 × 10(−5) were further evaluated in the replication data sets and combined by meta-analysis. RESULTS: Among 3145 patients with AD and 4213 controls lacking ε4 (mean [SD] age, 83.4 [7.6] years; 4363 [59.3.%] women), novel genome-wide significant associations were obtained in the discovery sample with rs536940594 in AC099552 (odds ratio [OR], 88.0; 95% CI, 9.08-852.0; P = 2.22 × 10(−7)) and rs138412600 in GPAA1 (OR, 1.78; 95% CI, 1.44-2.2; meta-P = 7.81 × 10(−8)). GPAA1 was also associated with expression in the brain of GPAA1 (β = −0.08; P = .03) and its repressive transcription factor, FOXG1 (β = 0.13; P = .003), and global cognition function (β = −0.53; P = .009). Significant gene-wide associations (threshold P ≤ 6.35 × 10(−7)) were observed for OR8G5 (P = 4.67 × 10(−7)), IGHV3-7 (P = 9.75 × 10(−16)), and SLC24A3 (P = 2.67 × 10(−12)) in 2377 patients with AD and 706 controls with ε4 (mean [SD] age, 75.2 [9.6] years; 1668 [54.1%] women). CONCLUSIONS AND RELEVANCE: The study identified multiple possible novel associations for AD with individual and aggregated rare variants in groups of individuals with and without APOE ε4 alleles that reinforce known and suggest additional pathways leading to AD.
Published: 2019

33. Serum magnesium and calcium levels in relation to ischemic stroke Mendelian randomization study

Author: Susanna C. Larsson, Matthew Traylor, Stephen Burgess, Giorgio B. Boncoraglio, Christina Jern, Karl Michaëlsson, Hugh S. Markus, Rainer Malik, Ganesh Chauhan, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne-Katrin Giese, Sander W van der Laan, Solveig Gretarsdottir, Christopher D Anderson, Michael Chong, Hieab HH Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, raci M Bartz, Oscar R Benavente, Steve Bevan, Giorgio B Boncoraglio, Robert D Brown, Adam S Butterworth, Caty Carrera, Cara L Carty, Daniel I Chasman, Wei-Min Chen, John W Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul IW de Bakker, Anita L DeStefano, Marcel den Hoed, Qing Duan, Stefan T Engelter, Guido J Falcone, Rebecca F Gottesman, Raji P Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B Harris, Ahamad Hassan, Aki S Havulinna, Susan R Heckbert, Elizabeth G Holliday, George Howard, Fang-Chi Hsu, Hyacinth I Hyacinth, M Arfan Ikram, Erik Ingelsson, Marguerite R Irvin, Xueqiu Jian, Jordi Jiménez-Conde, Julie A Johnson, J Wouter Jukema, Masahiro Kanai, Keith L Keene, Brett M Kissela, Dawn O Kleindorfer, Charles Kooperberg, Michiaki Kubo, Leslie A Lange, Carl D Langefeld, Claudia Langenberg, Lenore J Launer, Jin-Moo Lee, Robin Lemmens, Didier Leys, Cathryn M Lewis, Wei-Yu Lin, Arne G Lindgren, Erik Lorentzen, Patrik K Magnusson, Jane Maguire, Ani Manichaikul, Patrick F McArdle, James F Meschia, Braxton D Mitchell, Thomas H Mosley, Michael A Nalls, Toshiharu Ninomiya, Martin J O'Donnell, Bruce M Psaty, Sara L Pulit, Kristiina Rannikmäe, Alexander P Reiner, Kathryn M Rexrode, Kenneth Rice, Stephen S Rich, Paul M Ridker, Natalia S Rost, Peter M Rothwell, Jerome I Rotter, Tatjana Rundek, Ralph L Sacco, Saori Sakaue, Michele M Sale, Veikko Salomaa, Bishwa R Sapkota, Reinhold Schmidt, Carsten O Schmidt, Ulf Schminke, Pankaj Sharma, Agnieszka Slowik, Cathie LM Sudlow, Christian Tanislav, Turgut Tatlisumak, Kent D Taylor, Vincent NS Thijs, Gudmar Thorleifsson, Unnur Thorsteinsdottir, Steffen Tiedt, Stella Trompet, Christophe Tzourio, Cornelia M van Duijn, Matthew Walters, Nicholas J Wareham, Sylvia Wassertheil-Smoller, James G Wilson, Kerri L Wiggins, Qiong Yang, Salim Yusuf, Najaf Amin, Hugo S Aparicio, Donna K Arnett, John Attia, Alexa S Beiser, Claudine Berr, Julie E Buring, Mariana Bustamante, Valeria Caso, Yu-Ching Cheng, Seung Hoan Choi, Ayesha Chowhan, Natalia Cullell, Jean-François Dartigues, Hossein Delavaran, Pilar Delgado, Marcus Dörr, Gunnar Engström, Ian Ford, Wander S Gurpreet, Anders Hamsten, Laura Heitsch, Atsushi Hozawa, Laura Ibanez, Andreea Ilinca, Martin Ingelsson, Motoki Iwasaki, Rebecca D Jackson, Katarina Jood, Pekka Jousilahti, Sara Kaffashian, Lalit Kalra, Masahiro Kamouchi, Takanari Kitazono, Olafur Kjartansson, Manja Kloss, Peter J Koudstaal, Jerzy Krupinski, Daniel L Labovitz, Cathy C Laurie, Christopher R Levi, Linxin Li, Lars Lind, Cecilia M Lindgren, Vasileios Lioutas, Yong Mei Liu, Oscar L Lopez, Hirata Makoto, Nicolas Martinez-Majander, Koichi Matsuda, Naoko Minegishi, Joan Montaner, Andrew P Morris, Elena Muiño, Martina Müller-Nurasyid, Bo Norrving, Soichi Ogishima, Eugenio A Parati, Leema Reddy Peddareddygari, Nancy L Pedersen, Joanna Pera, Markus Perola, Alessandro Pezzini, Silvana Pileggi, Raquel Rabionet, Iolanda Riba-Llena, Marta Ribasés, Jose R Romero, Jaume Roquer, Anthony G Rudd, Antti-Pekka Sarin, Ralhan Sarju, Chloe Sarnowski, Makoto Sasaki, Claudia L Satizabal, Mamoru Satoh, Naveed Sattar, Norie Sawada, Gerli Sibolt, Ásgeir Sigurdsson, Albert Smith, Kenji Sobue, Carolina Soriano-Tárraga, Tara Stanne, O Colin Stine, David J Stott, Konstantin Strauch, Takako Takai, Hideo Tanaka, Kozo Tanno, Alexander Teumer, Liisa Tomppo, Nuria P Torres-Aguila, Emmanuel Touze, Shoichiro Tsugane, Andre G Uitterlinden, Einar M Valdimarsson, Sven J van der Lee, Henry Völzke, Kenji Wakai, David Weir, Stephen R Williams, Charles DA Wolfe, Quenna Wong, Huichun Xu, Taiki Yamaji, Dharambir K Sanghera, Olle Melander, Daniel Strbian, Israel Fernandez-Cadenas, W T Longstreth, Arndt Rolfs, Jun Hata, Daniel Woo, Jonathan Rosand, Guillaume Pare, Jemma C Hopewell, Danish Saleheen, Kari Stefansson, Bradford B Worrall, Steven J Kittner, Sudha Seshadri, Myriam Fornage, Hugh S Markus, Joanna MM Howson, Yoichiro Kamatani, Stephanie Debette, Martin Dichgans, Berr, Claudine, Unit of Cardiovascular and Nutritional Epidemiology [Stockholm, Sweden], Karolinska Institutet [Stockholm]-Institute of Environmental Medicine [Stockholm, Sweden], Stroke Research Group [London, UK] (Department of Brain Repair and Rehabilitation), University of London - UCL [London, UK], MRC Biostatistics Unit [Cambridge, UK], University of Cambridge [UK] (CAM), Department of Public Health and Primary Care [Cambridge, UK] (Institute of Public Health), Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Section of Clinical Immunology [Uppsala, Sweden] (Department of Immunology, Genetics and Pathology), Uppsala University, Department of Surgical Sciences [Uppsala, Sweden], This work was supported by the Swedish Research Council for Health, Working Life and Welfare (Forte) and the Swedish Research Council. Hugh Markus is supported by an NIHR Senior Investigator award. His and Matthew Traylor’s work is supported by infrastructural support from the Cambridge University Hospitals Trust NIHR Biomedical Research Centre., MEGASTROKE project of the International Stroke Genetics Consortium : Malik R, Chauhan G, Traylor M, Sargurupremraj M, Okada Y, Mishra A, Rutten-Jacobs L, Giese AK, van der Laan SW, Gretarsdottir S, Anderson CD, Chong M, Adams HH, Ago T, Almgren P, Amouyel P, Ay H, Bartz RM, Benavente OR, Bevan S, Boncoraglio GB, Brown RD Jr, Butterworth AS, Carrera C, Carty CL, Chasman DI, Chen WM, Cole JW, Correa A, Cotlarciuc I, Cruchaga C, Danesh J, de Bakker PI, DeStefano AL, Hoed MD, Duan Q, Engelter ST, Falcone GJ, Gottesman RF, Grewal RP, Gudnason V, Gustafsson S, Haessler J, Harris TB, Hassan A, Havulinna AS, Heckbert SR, Holliday EG, Howard G, Hsu FC, Hyacinth HI, Ikram MA, Ingelsson E, Irvin MR, Jian X, Jiménez-Conde J, Johnson JA, Jukema JW, Kanai M, Keene KL, Kissela BM, Kleindorfer DO, Kooperberg C, Kubo M, Lange LA, Langefeld CD, Langenberg C, Launer LJ, Lee JM, Lemmens R, Leys D, Lewis CM, Lin WY, Lindgren AG, Lorentzen E, Magnusson PK, Maguire J, Manichaikul A, McArdle PF, Meschia JF, Mitchell BD, Mosley TH, Nalls MA, Ninomiya T, O'Donnell MJ, Psaty BM, Pulit SL, Rannikmäe K, Reiner AP, Rexrode KM, Rice K, Rich SS, Ridker PM, Rost NS, Rothwell PM, Rotter JI, Rundek T, Sacco RL, Sakaue S, Sale MM, Salomaa V, Sapkota BR, Schmidt R, Schmidt CO, Schminke U, Sharma P, Slowik A, Sudlow CL, Tanislav C, Tatlisumak T, Taylor KD, Thijs VN, Thorleifsson G, Thorsteinsdottir U, Tiedt S, Trompet S, Tzourio C, van Duijn CM, Walters M, Wareham NJ, Wassertheil-Smoller S, Wilson JG, Wiggins KL, Yang Q, Yusuf S, Amin N, Aparicio HS, Arnett DK, Attia J, Beiser AS, Berr C, Buring JE, Bustamante M, Caso V, Cheng YC, Choi SH, Chowhan A, Cullell N, Dartigues JF, Delavaran H, Delgado P, Dörr M, Engström G, Ford I, Gurpreet WS, Hamsten A, Heitsch L, Hozawa A, Ibanez L, Ilinca A, Ingelsson M, Iwasaki M, Jackson RD, Jood K, Jousilahti P, Kaffashian S, Kalra L, Kamouchi M, Kitazono T, Kjartansson O, Kloss M, Koudstaal PJ, Krupinski J, Labovitz DL, Laurie CC, Levi CR, Li L, Lind L, Lindgren CM, Lioutas V, Liu YM, Lopez OL, Makoto H, Martinez-Majander N, Matsuda K, Minegishi N, Montaner J, Morris AP, Muiño E, Müller-Nurasyid M, Norrving B, Ogishima S, Parati EA, Peddareddygari LR, Pedersen NL, Pera J, Perola M, Pezzini A, Pileggi S, Rabionet R, Riba-Llena I, Ribasés M, Romero JR, Roquer J, Rudd AG, Sarin AP, Sarju R, Sarnowski C, Sasaki M, Satizabal CL, Satoh M, Sattar N, Sawada N, Sibolt G, Sigurdsson Á, Smith A, Sobue K, Soriano-Tárraga C, Stanne T, Stine OC, Stott DJ, Strauch K, Takai T, Tanaka H, Tanno K, Teumer A, Tomppo L, Torres-Aguila NP, Touze E, Tsugane S, Uitterlinden AG, Valdimarsson EM, van der Lee SJ, Völzke H, Wakai K, Weir D, Williams SR, Wolfe CD, Wong Q, Xu H, Yamaji T, Sanghera DK, Melander O, Jern C, Strbian D, Fernandez-Cadenas I, Longstreth WT Jr, Rolfs A, Hata J, Woo D, Rosand J, Pare G, Hopewell JC, Saleheen D, Stefansson K, Worrall BB, Kittner SJ, Seshadri S, Fornage M, Markus HS, Howson JM, Kamatani Y, Debette S, Dichgans M., Larsson, Susanna C [0000-0003-0118-0341], Apollo - University of Cambridge Repository, and Neurology
Subjects: medicine.medical_specialty, Neurology, Heredity, Neurologi, [SDV]Life Sciences [q-bio], chemistry.chemical_element, Calcium, Polymorphism, Single Nucleotide, Gastroenterology, Article, Brain Ischemia, Brain ischemia, 03 medical and health sciences, 0302 clinical medicine, Human genetics, Internal medicine, Mendelian randomization, Medicine, Humans, Magnesium, 030212 general & internal medicine, Stroke, Herència (Biologia), Genètica humana, business.industry, Neurosciences, Mendelian Randomization Analysis, Odds ratio, medicine.disease, Confidence interval, 3. Good health, [SDV] Life Sciences [q-bio], Intracranial Embolism, chemistry, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Neurology (clinical), business, 030217 neurology & neurosurgery, Neurovetenskaper
Abstract: Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.
Published: 2019
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34. Identification of additional risk loci for stroke and small vessel disease

Author: Matthew Traylor, Vilmundur Gudnason, Kerri L. Wiggins, Christophe Tzourio, Reinhold E. Schmidt, Hugo J. Aparicio, Tamara B. Harris, Audrey Y. Chu, Oscar R. Benavente, Anton J. M. de Craen, Nancy L. Pedersen, Lars Lannfelt, Didier Leys, Erkki Vartiainen, Myriam Fornage, Marileen L.P. Portegies, Nicholas L. Smith, Daniel Woo, Martin Dichgans, John W. Cole, Christina Jern, Christopher R Levi, Kenneth Rice, André G. Uitterlinden, Rebecca F. Gottesman, M. Arfan Ikram, Ralph L. Sacco, Cornelia M. van Duijn, Samuli Ripatti, Anita L. DeStefano, Donna K. Arnett, Curtis R. French, Tobias Kurth, Tomi Pastinen, Raji P. Grewal, Susan R. Heckbert, Jordi Jimenez-Conde, Jemma C. Hopewell, Cecilia M. Lindgren, Azadeh Reyahi, Michèle M. Sale, Marcello Ricardo Paulista Markus, Albert Hofman, Seung Hoan Choi, Peter J. Koudstaal, Veikko Salomaa, Robert Clarke, Arne Lindgren, B. Gwen Windham, Farid Radmanesh, Peter M. Rothwell, Carsten Oliver Schmidt, Xueqiu Jian, David S. Knopman, Yongmei Liu, Joan Montaner, Jean-François Dartigues, Paul M. Ridker, Julie A. Johnson, Stefan Gustafsson, Jerome I. Rotter, Manja Kloss, Tatjana Rundek, David J. Stott, Ganesh Chauhan, Ordan J. Lehmann, Ali Moussavi Nik, Marcel den Hoed, Alessandro Pezzini, Jin-Moo Lee, Hans J. Grabe, Sylvia Wassertheil-Smoller, Anders Hamsten, Thomas H. Mosley, Muralidharan Sargurupremraj, Lenore J. Launer, Kathryn M. Rexrode, Quenna Wong, Jonathan Rosand, David A. Bennett, Philip L. De Jager, James F. Meschia, Alexa S. Beiser, J. Wouter Jukema, Traci M. Bartz, Mike A. Nalls, Cathie Sudlow, Erik Ingelsson, Yoichiro Kamatani, Ulf Schminke, Joris Deelen, Stéphanie Debette, Andrew P. Morris, Aki S. Havulinna, Sudha Seshadri, Bradford B. Worrall, Stephen S. Rich, Lars Lindgren, Hieab H.H. Adams, Ani Manichaikul, Jean-Sébastien Vidal, Bruce M. Psaty, Julie E. Buring, Jean Dallongeville, Oscar L. Lopez, Corey R. Arnold, Olle Melander, Olafur Kjartansson, Alexander Teumer, Sarah J. Childs, William T. Longstreth, Charles C. White, Stefan T. Engelter, Daniel I. Chasman, Norrina B. Allen, Rainer Malik, Vincent Thijs, Stella Trompet, Joshua C. Bis, Ian Ford, Peter Carlsson, Céline Bellenguez, Sara L. Pulit, Pankaj Sharma, Patrik K. E. Magnusson, Flora Xue, Giorgio B. Boncoraglio, Mark Lathrop, Melissa E. Garcia, Andrew D. Johnson, Steve Bevan, Albert V. Smith, Claudia L. Satizabal, Agnieszka Slowik, Michael Griswold, Claudine Berr, and Hugh S. Markus
Subjects: Adult, Male, 0301 basic medicine, Adolescent, Population, Genome-wide association study, Biology, Bioinformatics, Article, Brain ischemia, Mice, Young Adult, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, medicine, Animals, Humans, Child, education, Allele frequency, Stroke, Aged, Aged, 80 and over, education.field_of_study, Cerebral infarction, Forkhead Transcription Factors, Odds ratio, Middle Aged, 16. Peace & justice, medicine.disease, R1, 3. Good health, Minor allele frequency, 030104 developmental biology, Genetic Loci, Cerebral Small Vessel Diseases, Child, Preschool, Female, Neurology (clinical), 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84â€ˆ961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45Â·8 years to 76Â·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at pâˆ’6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70â€ˆ804 participants, of whom 19â€ˆ816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at pâˆ’8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1Â·08, 95% CI 1Â·05â€“1Â·12, p=1Â·48â€ˆÃ—â€ˆ10âˆ’8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensityâ€”a marker of cerebral small vessel diseaseâ€”in stroke-free adults (n=21â€ˆ079; p=0Â·0025). Consistently, young patients (aged 2â€“32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2bâˆ’/âˆ’ cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.
Published: 2016
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35. GWAS for executive function and processing speed suggests involvement of the CADM2 gene

Author: Igor Rudan, Daniel I. Chasman, Helena Schmidt, Stefan Herms, Sharon L.R. Kardia, Oliver Stegle, Alison Pattie, Jenna Price, Gerardo Heiss, Karen A. Mather, L. J. Launer, Johan G. Eriksson, Christopher Oldmeadow, Ian Ford, Saira Saeed Mirza, Alan F. Wright, Ozren Polasek, Joshua M. Shulman, Maria K. Jonsdottir, André G. Uitterlinden, Rodney J. Scott, Kurt Lohman, Anita L. DeStefano, Peter W. Schofield, Perminder S. Sachdev, Stefania Bandinelli, Johan Wouter Jukema, John M. Starr, Rudolf S N Fehrmann, Y. C. Hsieh, William M. Meeks, Paul M. Ridker, R.G.J. Westendorp, Le Yu, J. C. van Swieten, Vilmundur Gudnason, Myriam Fornage, Melissa Garcia, Carla A. Ibrahim-Verbaas, James F. Wilson, Jean-Charles Lambert, Qiong Yang, Laura H. Coker, Stella Trompet, Lina Zgaga, Jennifer A. Smith, David J. Llewellyn, Nicole A. Kochan, Ben A. Oostra, Katja Petrovic, Peter Hoffmann, Qi Sun, James T. Becker, Najaf Amin, Vincent Chouraki, Brendan M. Buckley, D C Liewald, Jun Ding, Christiane Wolf, P. L. DeJager, Reinhold Schmidt, Chloe Fawns-Ritchie, Stéphanie Debette, Jing Wang, J. C. Bis, Nicola J. Armstrong, David J. Stott, Albert Hofman, Nazanin Karbalai, G. Eiriksdottir, Luke C. Pilling, D. S. Knopman, Maaike Schuur, Alexa S. Beiser, Annette L. Fitzpatrick, David A. Bennett, Aarno Palotie, Lude Franke, Sven Cichon, Mirna Kirin, Markus M. Nöthen, Thomas H. Mosley, Lynda M. Rose, Alan J. Gow, Caroline Hayward, Lori B. Chibnik, Ian J. Deary, Albert V. Smith, Jan Bressler, T.B. Harris, Stephen T. Turner, David J. Porteous, C M van Duijn, M. A. Ikram, Elizabeth G. Holliday, Mike A. Nalls, Luigi Ferrucci, Sudha Seshadri, Francine Grodstein, Marlene C. W. Stewart, Philip A. Wolf, Alexander Teumer, P.E. Slagboom, Jerome I. Rotter, Blair H. Smith, Juha Karjalainen, Susan M. Resnick, A.J.M. de Craen, Toshiko Tanaka, Alan D. Penman, Hans-Jörgen Grabe, Gary Davies, Oscar L. Lopez, Yongmei Liu, Kristine Yaffe, Veronique Vitart, Stela McLachlan, Katri Räikkönen, Rebecca F. Gottesman, Rhoda Au, Lynne J. Hocking, Carsten Oliver Schmidt, John Attia, Bruce M. Psaty, Wei Zhao, Jari Lahti, Epidemiology, Neurology, Clinical Genetics, Internal Medicine, [ 1 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Genet Epidemiol Unit, Rotterdam, Netherlands [ 2 ] Erasmus Univ, Med Ctr, Dept Neurol, Rotterdam, Netherlands [ 3 ] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Human Genet Ctr, Houston, TX 77030 USA [ 4 ] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA [ 5 ] Univ Bordeaux, Epidemiol & Biostat, U897, INSERM, Bordeaux, France [ 6 ] Bordeaux Univ Hosp, Dept Neurol, Bordeaux, France [ 7 ] Iceland Heart Assoc, Kopavogur, Iceland [ 8 ] Univ Iceland, Fac Med, Reykjavik, Iceland [ 9 ] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA [ 10 ] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh, Midlothian, Scotland [ 11 ] Leiden Univ, Med Ctr, Dept Cardiol, Leiden, Netherlands [ 12 ] Leiden Univ, Med Ctr, Dept Gerontol & Geriatr, Leiden, Netherlands [ 13 ] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA [ 14 ] Max Planck Inst Psychiat, RG Stat Genet, Munich, Germany [ 15 ] Brigham & Womens Hosp, Div Neurol, Program Translat Neuropsychiat Gen, Boston, MA 02115 USA [ 16 ] Wake Forest Sch Med, Dept Epidemiol, Winston Salem, NC USA [ 17 ] Univ Edinburgh, Inst Genet & Mol Med, MRC Human Genet Unit, Edinburgh, Midlothian, Scotland [ 18 ] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland [ 19 ] Med Univ & Gen Hosp Graz, Dept Neurol, Graz, Austria [ 20 ] Univ Split, Dept Publ Hlth, Split, Croatia [ 21 ] Trintiy Coll Dublin, Dept Publ Hlth & Primary Care, Dublin, Ireland [ 22 ] Res Ctr Juelich, Inst Neurosci & Med INM1, Julich, Germany [ 23 ] Univ Basel, Dept Biomed, Div Med Genet, Basel, Switzerland [ 24 ] Univ Bonn, Inst Human Genet, Life & Brain Res Ctr, Dept Genom, Bonn, Germany [ 25 ] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands [ 26 ] Univ Helsinki, Inst Behav Sci, Helsinki, Finland [ 27 ] Folkhalsan Res Ctr, Helsinki, Finland [ 28 ] Univ Exeter, Sch Med, Inst Biomed & Clin Sci, Exeter, Devon, England [ 29 ] Univ Med Greifswald, Inst Community Med, Greifswald, Germany [ 30 ] Univ New S Wales, UNSW Med, Sch Psychiat, Ctr Hlth Brain Ageing, Sydney, NSW, Australia [ 31 ] Univ Lille Nord France, Inst Pasteur Lille, U1167, INSERM, Lille, France [ 32 ] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 75 Francis St, Boston, MA 02115 USA [ 33 ] Harvard Univ, Sch Med, Boston, MA USA [ 34 ] NIA, Lab Behav Neurosci, NIH, Baltimore, MD 21224 USA [ 35 ] Brigham & Womens Hosp, Div Prevent Med, 75 Francis St, Boston, MA 02115 USA [ 36 ] Univ Newcastle, Hunter Med Res Inst, Newcastle, NSW 2300, Australia [ 37 ] Univ Newcastle, Fac Hlth, Newcastle, NSW 2300, Australia [ 38 ] Univ Dundee, Med Res Inst, Dundee, Scotland [ 39 ] NHLBI, Framingham Heart Study, Framingham, MA USA [ 40 ] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA [ 41 ] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands [ 42 ] Netherlands Consortium Hlth Ageing, Leiden, Netherlands [ 43 ] NIA, Lab Epidemiol & Populat Sci, Bethesda, MD 20892 USA [ 44 ] Univ Edinburgh, Dept Psychol, Edinburgh, Midlothian, Scotland [ 45 ] Wake Forest Sch Med, Div Publ Hlth Sci & Neurol, Winston Salem, NC USA [ 46 ] Max Planck Inst Intelligent Syst, Max Planck Inst Dev Biol, Tubingen, Germany [ 47 ] Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA [ 48 ] Univ Med Greifswald, Interfaculty Inst Genet & Funct Genom, Greifswald, Germany [ 49 ] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland [ 50 ] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA [ 51 ] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA [ 52 ] Landspitali Hosp, Reykjavik, Iceland Organization-Enhanced Name(s) Landspitali National University Hospital [ 53 ] NIA, Lab Neurogenet, Bethesda, MD 20892 USA [ 54 ] Mayo Clin, Dept Internal Med, Div Nephrol & Hypertens, Rochester, MN USA [ 55 ] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA [ 56 ] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA [ 57 ] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA USA [ 58 ] San Francisco VA Med Ctr, San Francisco, CA USA [ 59 ] Mayo Clin, Dept Neurol, Rochester, MN USA [ 60 ] Univ Mississippi, Med Ctr, Dept Med, Div Geriatr, Jackson, MS 39216 USA [ 61 ] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA [ 62 ] Univ Newcastle, Fac Hlth, Sch Med & Publ Hlth, Newcastle, NSW 2300, Australia [ 63 ] NIA, Translat Gerontol Branch, Baltimore, MD 21224 USA [ 64 ] Univ Glasgow, Dept Cardiovasc & Med Sci, Glasgow, Lanark, Scotland [ 65 ] Alzheimer Scotland Res Ctr, Edinburgh, Midlothian, Scotland [ 66 ] Univ Aberdeen, Div Appl Med, Aberdeen, Scotland [ 67 ] Garvan Inst Med Res, Canc Res Program, Sydney, NSW, Australia [ 68 ] Univ New S Wales, Sch Math & Stat, Sydney, NSW, Australia [ 69 ] Univ New S Wales, Prince Wales Clin Sch, Sydney, NSW, Australia [ 70 ] Baylor Coll Med, Dept Neurol, Houston, TX 77030 USA [ 71 ] Texas Childrens Hosp, Jan & Dan Duncan Neurol Res Inst, Dept Mol & Human Genet, Houston, TX 77030 USA [ 72 ] Univ Exeter, Sch Med, Epidemiol & Publ Hlth Grp, Exeter, Devon, England [ 73 ] Prince Wales Hosp, Neuropsychiat Inst, Sydney, NSW, Australia [ 74 ] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge, England [ 75 ] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland [ 76 ] Univ Helsinki, Dept Med Genet, Helsinki, Finland [ 77 ] Univ Cent Hosp, Helsinki, Finland [ 78 ] Taipei Med Univ, Sch Publ Hlth, Taipei, Taiwan [ 79 ] Univ Helsinki, Dept Gen Practice & Primary Hlth Care, Helsinki, Finland [ 80 ] Natl Inst Hlth & Welf, Helsinki, Finland [ 81 ] Univ Helsinki, Cent Hosp, Unit Gen Practice, Helsinki, Finland [ 82 ] Vasa Cent Hosp, Vaasa, Finland [ 83 ] Univ Mississippi, Med Ctr, Ctr Biostat & Bioinformat, Jackson, MS 39216 USA [ 84 ] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA [ 85 ] Rush Univ, Med Ctr, Rush Alzheimers Dis Ctr, Chicago, IL 60612 USA [ 86 ] Cedars Sinai Med Ctr, Med Genet Inst, Los Angeles, CA 90048 USA [ 87 ] Harbor UCLA Med Ctr, Angeles BioMed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA [ 88 ] Harbor UCLA Med Ctr, Dept Pediat, Div Genet Outcomes, Torrance, CA 90509 USA [ 89 ] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany [ 90 ] Leiden Univ, Med Ctr, Dept Mol Epidemiol, Leiden, Netherlands [ 91 ] Leiden Acad Vital & Ageing, Leiden, Netherlands [ 92 ] Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland [ 93 ] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands [ 94 ] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA [ 95 ] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA [ 96 ] Grp Hlth, Grp Hlth Res Inst, Seattle, WA USA [ 97 ] HELIOS Hosp Stralsund, Univ Med Greifswald, Dept Psychiat & Psychotherapy, Stralsund, Germany [ 98 ] Azienda Sanitaria Firenze, Geriatr Unit, Florence, Italy [ 99 ] Univ Edinburgh, Inst Genet & Mol Med, Ctr Genom & Expt Med, Edinburgh, Midlothian, Scotland [ 100 ] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Winston Salem, NC 27103 USA [ 101 ] Univ Texas Hlth Sci Ctr Houston, Inst Mol Med, Houston, TX 77030 USA [ 102 ] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA [ 103 ] Erasmus Univ, Med Ctr, Dept Radiol, Rotterdam, Netherlands [ 104 ] Univ Mississippi, Med Ctr, Dept Med & Neurol, Jackson, MS 39216 USA, Human genetics, Amsterdam Neuroscience - Neurodegeneration, Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Stem Cell Aging Leukemia and Lymphoma (SALL)
Subjects: 0301 basic medicine, Male, DISORDER, Trail Making Test, LOCI, Genome-wide association study, INTELLIGENCE, Neuropsychological Tests, Cohort Studies, Exon, Executive Function, 0302 clinical medicine, Cognition, SCHIZOPHRENIA, ONSET ALZHEIMERS-DISEASE, CADM2 protein, human, genetics [Cell Adhesion Molecules], gamma-Aminobutyric Acid, Genetics, Aged, 80 and over, PSC12, physiology [Cognition], COMMON VARIANTS, Genomics, Middle Aged, genetics [Genetic Variation], 3. Good health, physiology [Executive Function], Psychiatry and Mental health, genetics [European Continental Ancestry Group], Schizophrenia, Female, Psychology, EXPRESSION, genetics [White People], physiology [Cell Adhesion Molecules], Polymorphism, Single Nucleotide, White People, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Genetic variation, medicine, SNP, Humans, ddc:610, GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Genetic Association Studies, Aged, LINKAGE ANALYSIS, 9. Industry and infrastructure, Genetic Variation, medicine.disease, COGNITIVE FUNCTION, Introns, 030104 developmental biology, Cell Adhesion Molecules, 030217 neurology & neurosurgery, Stroop effect, Genome-Wide Association Study
Abstract: To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed. National Foundation for Alzheimer's disease and related disorders Institut Pasteur de Lille Centre National de Genotypage Inserm FRC (fondation pour la recherche sur le cerveau) Rotary LABEX (laboratory of excellence program investment for the future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease) MEDIALZ Project - ERDF (European Regional Development Fund) 11001003 Conseil Regional Nord Pas de Calais Fondation pour la Recherche Medicale Caisse Nationale Maladie des Travailleurs Salaries Direction Generale de la Sante MGEN Institut de la Longevite Agence Francaise de Securite Sanitaire des Produits de Sante Aquitaine and Bourgogne Regional Councils Fondation de France joint French Ministry of Research/INSERM 'Cohortes et collections de donnees biologiques' program Eisai Wellcome Trust British Heart Foundation Chief Scientist Office of the Scottish Executive NIA N01-AG-12100 National Heart, Lung and Blood Institute Contracts HHSN268201100005C HHSN268201100006C HHSN268201100007C HHSN268201100008C HHSN268201100009C HHSN268201100010C HHSN268201100011C HHSN268201100012C R01HL70825 R01HL087641 R01HL59367 R01HL086694 National Human Genome Research Institute U01HG004402 NIH Roadmap for Medical Research Austrian Science Fond (FWF) P20545-P05 P13180 Intramural Research Program of the NIH, National Institute on Aging NHLBI HHSN268201200036C HHSN268200800007C N01HC55222 N01HC85079 N01HC85080 N01HC85081 N01HC85082 N01HC85083 N01HC850863 U01HL080295 R01HL087652 R01HL105756 R01HL103612 R01HL120393 National Institute of Neurological Disorders and Stroke (NINDS) National Institute on Aging (NIA) R01AG023629 R01AG15928 R01AG20098 R01AG027058 National Center for Advancing Translational Sciences CTSI UL1TR000124 National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) DK063491 Medical Research Council (UK) European Commission Framework 6 project EUROSPAN LSHG-CT-2006-018947 Republic of Croatia Ministry of Science, Education and Sports 108-1080315-0302 Netherlands Organization for Scientific Research (NWO) Internationale Stichting Alzheimer Onderzoek (ISAO) Hersenstichting Nederland (HSN) Centre for Medical Systems Biology (CMSB) in the framework of the Netherlands Genomics Initiative (NGI) Russian Foundation for Basic Research (RFBR) National Heart, Lung and Blood Institute's Framingham Heart Study N01-HC-25195 Affymetrix, Inc N02-HL-6-4278 U01 HL096917 R01 HL093029 Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine Boston Medical Center National Institute of Neurological Disorders and Stroke NS17950 National Institute of Aging U01 AG049505 AG033193 AG008122 AG16495 Agence National de la Recherche Leducq Foundation National Heart, Lung and Blood Institute HL054464 HL054457 HL054481 HL071917 HL87660 HL043851 HL080467 National Institute of Neurological Disorders and Stroke of the National Institutes of Health NS041558 Chief Scientist Office of the Scottish Government Health Directorates CZD/16/6 Scottish Funding Council HR03006 Academy of Finland Finnish Diabetes Research Society Folkhalsan Research Foundation Novo Nordisk Foundation Finska Lakaresallskapet Signe and Ane Gyllenberg Foundation University of Helsinki Ministry of Education Ahokas Foundation Emil Aaltonen Foundation Juho Vainio Foundation Wellcome Trust WT089062 University of Newcastle's Strategic Initiative Fund Vincent Fairfax Family Foundation Hunter Medical Research Institute Italian Ministry of Health ICS 110.1RS97.71 US National Institute on Aging N01[AG]916413 N01[AG]821336 263 MD 9164 13 263 MD 821336 Intramural Research Program, National Institute on Aging, National Institutes of Health BBSRC Royal Society Chief Scientist Office of the Scottish Government Research Into Ageing UK Biotechnology and Biological Sciences Research Council (BBSRC) Engineering and Physical Sciences Research Council (EPSRC) Economic and Social Research Council (ESRC) MRC NHMRC 401184 Australian National Health & Medical Research Council 350833 568969 Capacity Building Grant 568940 NHMRC Project 525453 National Institutes of Health CA87969 CA49449 HL34594 U01HG004399 DK058845 CA65725 CA67262 CA50385 5UO1CA098233 EY09611 EY015473 HG004728 HL35464 CA55075 CA134958 DK070756 MRC Human Genetics Unit Arthritis Research UK European Union LSHG-CT-2006-018947 Bristol-Myers Squibb Netherlands Heart Foundation 2001 D 032 European commission 223004 Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) 050-060-810 Netherlands Organisation of Scientific Research NWO Investments 175.010.2005.011 911-03-012 Research Institute for Diseases in the Elderly 014-93-015 Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project 050-060-810 Erasmus Medical Center Erasmus University, Rotterdam Netherlands Organization for the Health Research and Development (ZonMw) Research Institute for Diseases in the Elderly (RIDE) Ministry of Education, Culture and Science Ministry for Health, Welfare and Sports European Commission 49 (DG XII) Municipality of Rotterdam ZonMW Veni Grant 916.13.054 NIA Grants P30AG10161 R01AG15819 R01AG17917 R01AG30146 K08AG34290 K25AG41906 Federal Ministry of Education and Research 01ZZ9603 01ZZ0103 01ZZ0403 Ministry of Cultural Affairs Social Ministry of the Federal State of Mecklenburg-West Pomerania National Cancer Institute CA047988 Donald W Reynolds Foundation Fondation Leducq Amgen info:eu-repo/grantAgreement/EC/FP7/223004
Published: 2016
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36. Genome-wide linkage analyses of non-Hispanic white families identify novel loci for familial late-onset Alzheimer's disease

Author: James Jaworski, Jeffrey M. Vance, Regina M. Carney, Margaret A. Pericak-Vance, Jonathan L. Haines, Gerard D. Schellenberg, Laura S. Cantwell, Thomas D. Bird, Gary W. Beecham, Sandra Barral, Anita L. DeStefano, Michael L. Cuccaro, Wendy H. Raskind, Tatiana Foroud, Eden R. Martin, Lindsay A. Farrer, Badri N. Vardarajan, Brian W. Kunkle, Alison Goate, Richard Mayeux, and Amanda Partch
Subjects: 0301 basic medicine, Genetic Linkage, Epidemiology, Clinical Neurology, Locus (genetics), Genome-wide association study, Biology, Identity by descent, White People, Article, 03 medical and health sciences, Late-onset Alzheimer's disease, Cellular and Molecular Neuroscience, Apolipoproteins E, Familial, Developmental Neuroscience, Alzheimer Disease, Genetic linkage, Gene cluster, medicine, Genetics, Humans, Genetic Predisposition to Disease, Allele, High penetrance, Gene, Aged, Aged, 80 and over, Linkage, Health Policy, Middle Aged, medicine.disease, Pedigree, Non-Hispanic white, Psychiatry and Mental health, 030104 developmental biology, Neurology (clinical), Alzheimer's disease, Geriatrics and Gerontology, Genome-Wide Association Study
Abstract: Introduction Few high penetrance variants that explain risk in late-onset Alzheimer's disease (LOAD) families have been found. Methods We performed genome-wide linkage and identity-by-descent (IBD) analyses on 41 non-Hispanic white families exhibiting likely dominant inheritance of LOAD, and having no mutations at known familial Alzheimer's disease (AD) loci, and a low burden of APOE e4 alleles. Results Two-point parametric linkage analysis identified 14 significantly linked regions, including three novel linkage regions for LOAD (5q32, 11q12.2–11q14.1, and 14q13.3), one of which replicates a genome-wide association LOAD locus, the MS4A6A-MS4A4E gene cluster at 11q12.2. Five of the 14 regions (3q25.31, 4q34.1, 8q22.3, 11q12.2–14.1, and 19q13.41) are supported by strong multipoint results (logarithm of odds [LOD*] ≥1.5). Nonparametric multipoint analyses produced an additional significant locus at 14q32.2 (LOD* = 4.18). The 1-LOD confidence interval for this region contains one gene, C14orf177 , and the microRNA Mir_320 , whereas IBD analyses implicates an additional gene BCL11B , a regulator of brain-derived neurotrophic signaling, a pathway associated with pathogenesis of several neurodegenerative diseases. Discussion Examination of these regions after whole-genome sequencing may identify highly penetrant variants for familial LOAD.
Published: 2016
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37. Network analysis of drug effect on triglyceride-associated DNA methylation

Author: Anita L. DeStefano, Elise Lim, Gina M. Peloso, Achilleas N. Pitsillides, Jiayi Wu, L. Adrienne Cupples, Daniel Posner, Ching-Ti Liu, Hanfei Xu, and Peitao Wu
Subjects: 0301 basic medicine, lcsh:R, lcsh:Medicine, General Medicine, Methylation, Computational biology, Biology, Phenotype, General Biochemistry, Genetics and Molecular Biology, 3. Good health, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Proceedings, CpG site, 030220 oncology & carcinogenesis, DNA methylation, Gene expression, lcsh:Q, Epigenetics, lcsh:Science, Gene, Quantile normalization
Abstract: Background DNA methylation, an epigenetic modification, can be affected by environmental factors and thus regulate gene expression levels that can lead to alterations of certain phenotypes. Network analysis has been used successfully to discover gene sets that are expressed differently across multiple disease states and suggest possible pathways of disease progression. We applied this framework to compare DNA methylation levels before and after lipid-lowering medication and to identify modules that differ topologically between the two time points, revealing the association between lipid medication and these triglyceride-related methylation sites. Methods We performed quality control using beta-mixture quantile normalization on 463,995 cytosine-phosphate-guanine (CpG) sites and deleted problematic sites, resulting in 423,004 probes. We identified 14,850 probes that were nominally associated with triglycerides prior to treatment and performed weighted gene correlation network analysis (WGCNA) to construct pre- and posttreatment methylation networks of these probes. We then applied both WGCNA module preservation and generalized Hamming distance (GHD) to identify modules with topological differences between the pre- and posttreatment. For modules with structural changes between 2 time points, we performed pathway-enrichment analysis to gain further insight into the biological function of the genes from these modules. Results Six triglyceride-associated modules were identified using pretreatment methylation probes. The same 3 modules were not preserved in posttreatment data using both the module-preservation and the GHD methods. Top-enriched pathways for the 3 differentially methylated modules are sphingolipid signaling pathway, proteoglycans in cancer, and metabolic pathways (p values
Published: 2018

38. P1‐156: GENE‐BASED ANALYSES IN WHOLE GENOME SEQUENCING OF FAMILIAL LATE‐ONSET ALZHEIMER'S DISEASE

Author: Anita L. DeStefano, Badri N. Vardarajan, Timothy A. Thornton, Elizabeth Blue, James M. Jaworski, Rafael Lantigua, Cornelia M. van Duijn, Li-San Wang, Haines Jl, Martin Medrano, Gary W. Beecham, Ellen M. Wijsman, Giuseppe Tosto, Eric Boerwinkle, Gerard D. Schellenberg, William S. Bush, Richard Mayeux, Sandra Barral, Dolly Reyes-Dumeyer, Alison Goate, Margaret A. Pericak-Vance, Adam C. Naj, Lisa M. Brown, Lindsay A. Farrer, and Eden R. Martin
Subjects: Whole genome sequencing, Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Late onset, Neurology (clinical), Disease, Geriatrics and Gerontology, Biology, Gene
Published: 2018
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39. P2‐111: INTERACTION BETWEEN ALZHEIMER'S DISEASE GENETIC RISK SCORE AND MIDLIFE PLASMA LIPID LEVELS ON ALZHEIMER ’S DISEASE IN THE FRAMINGHAM HEART STUDY

Author: Gina M. Peloso, Anita L. DeStefano, Alexa S. Beiser, and Sudha Seshadri
Subjects: medicine.medical_specialty, Epidemiology, business.industry, Health Policy, Disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Framingham Heart Study, Developmental Neuroscience, Internal medicine, Plasma lipids, Cardiology, Medicine, Neurology (clinical), Geriatrics and Gerontology, Genetic risk, business
Published: 2018
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40. P1‐149: THE ALZHEIMER'S DISEASE SEQUENCING PROJECT (ADSP) DATA UPDATE 2018

Author: Jason Waligorski, John J. Farrell, Eric Boerwinkle, Yuk Yee Leung, Laura B. Cantwell, Amanda B. Kuzma, Seung Hoan Choi, Sudha Seshadri, Elizabeth L. Appelbaum, Tatiana Foroud, Adam C. Naj, Namrata Gupta, Gerard D. Schellenberg, Kelley Faber, Otto Valladares, Joshua C. Bis, Li-San Wang, Liming Qu, Kara L. Hamilton-Nelson, Anita L. DeStefano, Yi Zhao, Donna M. Muzny, Briana Vogel, Robert S. Fulton, Dolly Reyes-Dumeyer, and William J Salerno
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Neurology (clinical), Computational biology, Disease, Geriatrics and Gerontology, business
Published: 2018
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41. O3‐06‐01: WHOLE EXOME SEQUENCING STUDY IDENTIFIES RARE COPY NUMBER VARIATIONS FOR LATE‐ONSET ALZHEIMER'S DISEASE: THE ALZHEIMER'S DISEASE SEQUENCING PROJECT CASE‐CONTROL ANALYSIS

Author: Sudha Seshadri, Kim C. Worley, Xueqiu Jian, Theodore Chiang, Eric Boerwinkle, Myriam Fornage, Joshua C. Bis, William J. Salerno, and Anita L. DeStefano
Subjects: Genetics, Epidemiology, Health Policy, Late onset, Disease, Biology, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Case control analysis, Neurology (clinical), Copy-number variation, Geriatrics and Gerontology, Exome sequencing
Published: 2018
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42. Quality Control and Integration of Genotypes from Two Calling Pipelines for Whole Genome Sequence Data in the Alzheimer’s Disease Sequencing Project

Author: Gerard D. Schellenberg, Alejandro Q. Nato, Daniel C. Koboldt, Kara L. Hamilton-Nelson, Honghuang Lin, Badri N. Vardarajan, Seung Hoan Choi, Alzheimer’s Disease Sequencing, Harkirat Sohi, Cornelia M. van Duijn, John Malamon, Michael A. Schmidt, Daniel Lancour, Fangui Sun, Simon White, Anita L. DeStefano, William J Salerno, Eden R. Martin, Sven J. van der Lee, Bowen Wang, Josée Dupuis, Joshua C. Bis, Li-San Wang, William S. Bush, Sudha Seshadri, Ellen M. Wijsman, Brian W. Kunkle, Adam C. Naj, Namrata Gupta, Amanda B. Kuzma, Najaf Amin, L. Adrienne Cupples, Mohamad Saad, Eric Boerwinkle, Yiyi Ma, Mariusz Butkiewicz, Neurology, Amsterdam Neuroscience - Neurodegeneration, and Epidemiology
Subjects: 0106 biological sciences, Male, Quality Control, Genotype, Genotyping Techniques, Disease, Computational biology, Biology, 01 natural sciences, Article, 03 medical and health sciences, symbols.namesake, Alzheimer Disease, Genetics, Humans, Multiplex, Indel, 030304 developmental biology, Whole genome sequencing, 0303 health sciences, Variant Call Format, Polymorphism, Genetic, Whole Genome Sequencing, Mendelian inheritance, symbols, Female, Algorithms, 010606 plant biology & botany, Genome-Wide Association Study
Abstract: The Alzheimer’s Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed “consensus calling,” to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.AbbreviationsAD, Alzheimer’s disease; QC, Quality Control; LSSAC, Large-Scale Sequencing and Analysis Center; Broad, Broad Institute Genomics Service; Baylor, Baylor College of Medicine Human Genome Sequencing Center; WashU, Washington University-St. Louis McDonnell Genome Institute; WGS, whole genome sequencing; WES, whole exome sequencing; indel, insertion-deletion variants; VCF, variant control format; MI, Mendelian inconsistency; MC, Mendelian consistency; GWAS, genome-wide association study; VR, referent allele read depth; DP, overall read depth; MS, mapping score; GQ, genotype quality score; Ti/Tv, Transition/Transversion; CS, concordance code
Published: 2018
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43. Genetic Variation in Genes Underlying Diverse Dementias May Explain a Small Proportion of Cases in the Alzheimer's Disease Sequencing Project

Author: William J Salerno, Christiane Reitz, Josée Dupuis, Richard Mayeux, Sudha Seshadri, Badri N. Vardarajan, Gerard D. Schellenberg, Lindsay A. Farrer, Elizabeth E. Blue, Ellen M. Wijsman, Dolly Reyes, Harkirat Sohi, Kathryn L. Lunetta, Yiyi Ma, Otto Valadares, Eden R. Martin, Sandra Barral, Anita L. DeStefano, Carlos Cruchaga, Eric Boerwinkle, Joshua C. Bis, Li-San Wang, Gyungah Jun, Alison Goate, Mariusz Butkiewicz, Jenny Lee, Patrick A. Navas, Margaret A. Pericak-Vance, Michael O. Dorschner, Gary W. Beecham, William S. Bush, Jennifer E. Below, Timothy A. Thornton, Brian W. Kunkle, Alejandro Q. Nato, Adam C. Naj, Jim Jaworski, Amanda B. Kuzma, Debby W. Tsuang, Hiep Nguyen, Cornelia M. van Duijn, Jonathan L. Haines, and Epidemiology
Subjects: Male, 0301 basic medicine, Apolipoprotein E, Cognitive Neuroscience, Nerve Tissue Proteins, Disease, Biology, Polymorphism, Single Nucleotide, Article, Cohort Studies, Novel gene, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Genetic variation, Prevalence, medicine, PSEN1, Humans, Dementia, Gene, Aged, Aged, 80 and over, Genetics, TREM2, Genetic Variation, Sequence Analysis, DNA, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Female, Geriatrics and Gerontology, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Background/Aims: The Alzheimer’s Disease Sequencing Project (ADSP) aims to identify novel genes influencing Alzheimer’s disease (AD). Variants within genes known to cause dementias other than AD have previously been associated with AD risk. We describe evidence of co-segregation and associations between variants in dementia genes and clinically diagnosed AD within the ADSP. Methods: We summarize the properties of known pathogenic variants within dementia genes, describe the co-segregation of variants annotated as “pathogenic” in ClinVar and new candidates observed in ADSP families, and test for associations between rare variants in dementia genes in the ADSP case-control study. The participants were clinically evaluated for AD, and they represent European, Caribbean Hispanic, and isolate Dutch populations. Results/Conclusions: Pathogenic variants in dementia genes were predominantly rare and conserved coding changes. Pathogenic variants within ARSA, CSF1R, and GRN were observed, and candidate variants in GRN and CHMP2B were nominated in ADSP families. An independent case-control study provided evidence of an association between variants in TREM2, APOE, ARSA, CSF1R, PSEN1, and MAPT and risk of AD. Variants in genes which cause dementing disorders may influence the clinical diagnosis of AD in a small proportion of cases within the ADSP.
Published: 2018

44. Evaluation of power of the Illumina HumanOmni5M-4v1 BeadChip to detect risk variants for human complex diseases

Author: Philip A. Wolf, Yi-Hsiang Hsu, Sudha Seshadri, Anita L. DeStefano, Nancy L. Heard-Costa, Chuanhua Xing, Douglas P. Kiel, Josée Dupuis, Jie Huang, and L. Adrienne Cupples
Subjects: 0301 basic medicine, Genotyping Techniques, Quantitative Trait Loci, Single-nucleotide polymorphism, Genome-wide association study, Computational biology, Quantitative trait locus, Biology, Hippocampus, Sensitivity and Specificity, Article, 03 medical and health sciences, Bone Density, Genetics, Humans, Genetic Testing, International HapMap Project, 1000 Genomes Project, Genotyping, Genetics (clinical), Oligonucleotide Array Sequence Analysis, Organ Size, Minor allele frequency, 030104 developmental biology, Mutation, Imputation (genetics), Genome-Wide Association Study
Abstract: Although emerging sequencing technologies can characterize all genetic variants, the cost is still high. Illumina released the HumanOmni5M-4v1 (Omni5) genotype array with ~4.3M assayed SNPs, a much denser array compared with other available arrays. The Omni5 balances both cost and array density. In this article, we illustrate the power of Omni5 to detect genetic associations. The Omni5 includes variants with a wide range of minor allele frequencies down to
Published: 2015
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45. Convergent genetic and expression data implicate immunity in Alzheimer's disease

Author: John R. Gilbert, Simon Lovestone, Diana Zelenika, Walter A. Kukull, Peter Passmore, Chiao-Feng Lin, Nathalie Fievet, Brian W. Kunkle, Dominique Campion, Philip L. De Jager, Adam C. Naj, Kara L. Hamilton-Nelson, Lina Keller, Jean-Charles Lambert, Denise Harold, Paul K. Crane, John Powell, Kathryn L. Lunetta, Paolo Caffarra, Lei Yu, Anthony Bayer, Tricia A. Thornton-Wells, Christiane Reitz, Eric B. Larson, Florentino Sanchez Garcia, Lindsay A. Farrer, Charlene Thomas, Ekaterina Rogaeva, Victoria Alavarez, Alfredo Ramirez, Pascale Barberger-Gateau, Dan Rujescu, Paul Hollingworth, Margaret A. Pericak-Vance, Daniela Galimberti, J. Kornhuber, Alexey Vedernikov, Philippe Amouyel, Peter Holmans, Gianfranco Spalletta, Carole Dufouil, Wolfgang Maier, Patrick G. Kehoe, Florence Pasquier, Lesley Jones, Harald Hampel, Stephen Todd, Valur Emilsson, Pau Pastor, Manuel Mayhaus, Claudine Berr, Seth Love, Michelangelo Mancuso, Mikko Hiltunen, Simon Mead, Hilkka Soininen, Vincent Deramecourt, Bernadette McGuinness, Magda Tsolaki, Jean-François Dartigues, Jordi Clarimón, Marie-Thérèse Bihoreau, Laura Fratiglioni, Duane Beekly, Sabrina Pichler, Caroline Graff, Albert V. Smith, Nick C. Fox, Amy Gerrish, Karen Ritchie, Carlos Cruchaga, John Hardy, Benedetta Nacmias, Maria Candida Deniz Naranjo, Christine Van Broeckhoven, Laura B. Cantwell, Minerva M. Carrasquillo, Richard Mayeux, Karolien Bettens, Vincent Chouraki, Clive Holmes, Thomas H. Mosley, David C. Rubinsztein, Gyungah Jun, Anita L. DeStefano, Lenore J. Launer, Alexander Richards, Jerome I. Rotter, Lars Lannfelt, Annette L. Fitzpatrick, Fanggeng Zou, Joseph D. Buxbaum, Cristina Razquin, Mercè Boada, Najaf Amin, Palmi V. Jonsson, Martin Dichgans, Thomas J. Montine, Yoichiro Kamatani, Debby W. Tsuang, Alexis Brice, Hakon Hakonarson, John Collinge, Albert Hofman, Eden R. Martin, Oscar L. Lopez, Olivier Hanon, Melanie L. Dunstan, Kevin Morgan, Nicola Jones, Cornelia M. van Duijn, Valentina Escott-Price, Vilmundur Gudnason, Susanne Moebus, Peter St George-Hyslop, Michael Conlon O'Donovan, Michael Gill, Tim Becker, Markus M. Nöthen, Sandro Sorbi, Céline Bellenguez, Mike A. Nalls, Martin Ingelsson, Otto Valladares, Kristel Sleegers, Sudha Seshadri, Gerard D. Schellenberg, María J. Bullido, Patrizia Mecocci, Eric Boerwinkle, Michael John Owen, Helena Schmidt, Kristelle Brown, Julie Williams, Renée F.A.G. de Bruijn, Jonathan L. Haines, Mark Lathrop, Maria Del Zompo, Denis A. Evans, Rebecca Sims, Badri N. Vardarajan, John S. K. Kauwe, Luc Letteneur, Agustín Ruiz, David Craig, Steven G. Younkin, Bruce M. Psaty, Ignacio Mateo, Tatiana Foroud, David Wallon, P. Bosco, Alberti Lleò, Amanda J. Myers, Alberto Pilotto, Petra Proitsi, Reinhold Schmidt, Matthew J. Huentelman, David A. Bennett, Onofre Combarros, Kelley Faber, Gudny Eiriksdottir, M. Arfan Ikram, Lluís Tárraga, Francesco Panza, Carla A. Ibrahim-Verbaas, Joshua C. Bis, Li-San Wang, Matthias Riemenschneider, Gary W. Beecham, Alison Goate, Seung Hoan Choi, John Gallacher, Robert Clarke, Didier Hannequin, Deborah Blacker, Frank Jessen, Christophe Tzourio, Tamara B. Harris, Benjamin Grenier-Boley, Paola Bossù, Janet A. Johnston, M. Ilyas Kamboh, Giancarlo Russo, Timothy Stone, Carol Brayne, Eliecer Coto, French National Foundation on Alzheimer’s Disease and Related Disorders, Institut Pasteur, National Institutes of Health (US), Centre National de Genotypage (France), Fédération pour la Recherche sur le Cerveau (France), Erasmus University Rotterdam, Medical Research Council (UK), International Genomics of Alzheimer's Disease Consortium (IGAP), Neurology, and Epidemiology
Subjects: Pathway analysis, Epidemiology, ALIGATOR, Alzheimer's disease, Cholesterol metabolism, Dementia, Endocytosis, Immune response, Neurodegeneration, Ubiquitination, Weighted gene co-expression network analysis, Medizin, Genome-wide association study, genetics [Alzheimer Disease], Gene expression, Genetics, education.field_of_study, Health Policy, Brain, Single Nucleotide, 3. Good health, Psychiatry and Mental Health, Algorithms, Alzheimer Disease, Genome-Wide Association Study, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Developmental Neuroscience, Neurology (clinical), Geriatrics and Gerontology, Cellular and Molecular Neuroscience, Alzheimer’s disease, metabolism [Alzheimer Disease], Population, Genomics, Biology, Aligator, Article, Biological pathway, SDG 3 - Good Health and Well-being, medicine, ddc:610, Polymorphism, education, medicine.disease, Protein ubiquitination, metabolism [Brain], Human medicine
Abstract: © 2015, Elsevier Inc. All rights reserved. Background: Late-onset Alzheimer's disease (AD) is heritable with 20 genes showing genome-wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10-12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10-11), cholesterol transport (P = 2.96 × 10-9), and proteasome-ubiquitin activity (P = 1.34 × 10-6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P =.002-.05). Conclusions: The immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics., Medical Research Council, Alzheimer’s Research UK, and theWelsh Assembly Government. ADGC and CHARGE were supported by the National Institutes of Health, National Institute on Aging (NIH-NIA). CHARGE was also supported by Erasmus Medical Center and Erasmus University. IGAP was funded by the French National Foundation on Alzheimer’s Disease and Related Disorders, the Centre National de Genotypage and the Institut Pasteur de Lille, Inserm, FRC (Fondation pour la Recherche sur le Cerveau), and Rotary. This work has been developed and supported by the LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease).
Published: 2015
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46. Plasma amyloid β levels are driven by genetic variants nearAPOE, BACE1, APP, PSEN2:A genome-wide association study in over 12,000 non-demented participants

Author: Sven J. van der Lee, Eric Boerwinkle, Alexa S. Beiser, Myriam Fornage, Phil de Jager, Maria J. Knol, Natalie Terzikhan, Jeannette Simino, Cornelia M. van Duijn, Vincent Chouraki, Najaf Amin, Megan L. Grove, Jean-Charles Lambert, Alzheimer’s Disease Neuroimaging Initiative, Christophe Tzourio, M. Arfan Ikram, Benjamin Grenier-Boley, Sudha Seshadri, Thomas H. Mosley, David S. Knopman, Philippe Amouyel, Charles DeCarli, André G. Uitterlinden, Charles C. White, Shuo Li, Jean-François Dartigues, Rebecca F. Gottesman, Christiane Reitz, Vincent Damotte, Anita L. DeStefano, Hieab H.H. Adams, Qiong Yang, Carlos Cruchaga, Steven G. Younkin, Susanna Schraen, Luc Buée, Claudine Berr, Giuseppe Tosto, Jan Bressler, and Claudia L. Satizabal
Subjects: Apolipoprotein E, Genetics, 0303 health sciences, education.field_of_study, Population, Genome-wide association study, Biology, 03 medical and health sciences, 0302 clinical medicine, Endophenotype, PSEN2, Biomarker (medicine), education, Gene, 030217 neurology & neurosurgery, 030304 developmental biology, Genetic association
Abstract: INTRODUCTIONThere is increasing interest in plasma Aβ as an endophenotype and biomarker of Alzheimer’s disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important processes that determine plasma Aβ measures.METHODSWe included 12,369 non-demented participants derived from eight population-based studies. Imputed genetic data and plasma Aβ1-40, Aβ1-42 levels and Aβ1-42/Aβ1-40 ratio were used to perform genome-wide association studies, gene-based and pathway analyses. Significant variants and genes were followed-up for the association with PET Aβ deposition and AD risk.RESULTSSingle-variant analysis identified associations acrossAPOEfor Aβ1-42 and Aβ1-42/Aβ1-40 ratio, andBACE1for Aβ1-40. Gene-based analysis of Aβ1-40 additionally identified associations forAPP,PSEN2,CCKandZNF397. There was suggestive interaction between aBACE1variant andAPOEε4 on brain Aβ deposition.DISCUSSIONIdentification of variants near/in known major Aβ-processing genes strengthens the relevance of plasma-Aβ levels both as an endophenotype and a biomarker of AD.
Published: 2017
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47. Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Author: John Hardy, Nick C. Fox, Lena Lilius, Christine Van Broeckhoven, Mindy J. Katz, Carlos Cruchaga, Joshua W. Miller, Carol Brayne, Letizia Concari, Christopher Shaw, Minerva M. Carrasquillo, Richard Mayeux, Anne Boland, Charles DeCarli, Helena C. Chui, Laura B. Cantwell, Yoland Aladro Benito, Chuang Kuo Wu, Elaine R. Peskind, Andrew McDavid, M. Ilyas Kamboh, Amanda Smith, Pascual Sánchez-Juan, Jean-François Deleuze, Jayanadra J. Himali, Thomas H. Mosley, Thomas J. Montine, Chuanhai Cao, Andreas J. Forstner, Thomas G. Beach, Robert Barber, Miquel Aguilar, Liming Qu, Jerome I. Rotter, Matthew J. Huentelman, Christiane Reitz, Christopher J. O'Donnell, Steven G. Younkin, Bradley T. Hyman, Bruce L. Miller, Rachelle S. Doody, Eric B. Larson, Ronald L. Hamilton, Todd E. Golde, Steven E. Arnold, Melissa E. Garcia, Rachel Raybould, Lena Kilander, Mark A. Sager, Kevin Morgan, Kathryn L. Lunetta, William Perry, Joseph D. Buxbaum, Craig S. Atwood, Thomas D. Bird, Michael Conlon O'Donovan, Robert Olaso, Juan Fortea, Susanne Moebus, Lisa L. Barnes, Rachel Marshall, Huntington Potter, Mercè Boada, Shahzad Ahmad, Paolo Caffarra, Daniel C. Marson, Jonathan L. Haines, Perrie M. Adams, John M Olichney, Lars Lannfelt, Stefanie Heilmann-Heimbach, Markus M. Nöthen, Shubhabrata Mukherjee, John Malamon, Xue Wang, Christopher S. Carlson, Karen Ritchie, Roger N. Rosenberg, Paul K. Crane, Alexa S. Beiser, Céline Bellenguez, Robert C. Green, Maria Urbano, Petra Proitsi, John Powell, Elisa Majounie, Ammar Al-Chalabi, Hakon Hakonarson, Yogen Patel, Martin Scherer, Julie Williams, Richard B. Lipton, Vincent Dermecourt, Adam L. Boxer, Gerard D. Schellenberg, David G. Clark, Anita L. DeStefano, Joel H. Kramer, Victoria Alvarez, Nandini Badarinarayan, Oscar L. Lopez, Chris Corcoran, Ubaldo Bonuccelli, Donald R. Royall, James Bowen, Monica Diez Fairen, Tricia A. Thornton-Wells, Nilufer Ertekin-Taner, Florence Pasquier, Martin Ingelsson, Yi Zhao, John R. Gilbert, Valentina Escott-Price, Amanda B. Kuzma, Fabienne Garzia, Reinhard Heun, Otto Valladares, Andrew J. Saykin, Sara Ortega-Cubero, Liana G. Apostolova, Henry L. Paulson, John K Kauwe, Imelda Barber, Carolina Ceballos Diaz, Douglas Galasko, M. Arfan Ikram, Lluís Tárraga, Carlo Caltagirone, Joan S. Reisch, Wolfgang Maier, Bruno Vellas, Rebecca Sims, Angela Hodges, Matthew P. Frosch, Isabel Henández, Annakaisa Haapasalo, Thor Aspelund, Håkan Thonberg, Aimee Pierce, Roger L. Albin, Wayne W. Poon, Rebecca Sussams, Amy Braddel, Ranjan Duara, Albert V. Smith, Kirk C. Wilhelmsen, Gianfranco Spalletta, Simon Lovestone, Peter Passmore, Ana Frank-García, Cynthia M. Carlsson, Jade Chapman, Nathan D. Price, Philip L. De Jager, John M. Ringman, Seung Hoan Choi, Nicola Denning, Michael John Owen, Clinton T. Baldwin, Amalia C. Bruni, Denis A. Evans, Rudolph E. Tanzi, Dominique Campion, Laura Fratiglioni, Alberto Lleó, Per Hoffmann, Carole Dufouil, Charlotte Forsell, Alun Meggy, Charlene Thomas, Robert S. Stern, James B. Leverenz, Tatiana Foroud, William W. Seeley, James J. Lah, Brian A. Lawlor, Kenneth B. Fallon, Matthias Riemenschneider, Ryan M. Huebinger, Regina M. Carney, Clinton B. Wright, Didier Hannequin, Deborah Blacker, Anne Kinhult-Ståhlbom, Ekaterina Rogaeva, Andrew P. Lieberman, Bernardino Ghetti, Linda J. Van Eldik, Bernadette McGuinness, Thomas Fairchild, Margaret A. Pericak-Vance, Ashok Raj, Reinhold Schmidt, Ronald C. Petersen, Harald Hampel, María J. Bullido, Steven L. Carroll, Maria Candida Deniz Naranjo, Kathleen A. Welsh-Bohmer, Myriam Fornage, Joseph F. Quinn, Caroline Graff, Claudia L. Satizabal, Patrice L. Whitehead, David Wallon, Christopher Medway, Lindsay A. Farrer, Vilmundur Gudnason, Peter St George-Hyslop, Pau Pastor, Frank Jessen, Erin L. Abner, Johanna Jakobsdottir, Hieab H.H. Adams, Roberta Cecchetti, Walter A. Kukull, Thomas S. Wingo, Michelle K. Lupton, Valur Emilsson, Susan M. McCurry, Simon Mead, Hilkka Soininen, Sandra Weintraub, Amy Gerrish, Lindy E. Harrell, Lina Keller, Jean-Charles Lambert, Denise Harold, Stephen Todd, Wei Gu, Maura Gallo, Najaf Amin, Lenore J. Launer, Eleonora Sacchinelli, Mikko Hiltunen, Cécile Dulary, Eliecer Coto, Xueqiu Jian, Nathalie Fievet, Patrizia Mecocci, Sarah Taylor, Eric Boerwinkle, Maria Serpente, Ronald G. Munger, Ina Giegling, Carlo Masullo, Aoibhinn Lynch, Eliezer Masliah, Anne M. Koivisto, Chang En Yu, Qiong Yang, Benedetta Nacmias, Wayne C. McCormick, Kristelle Brown, Alessio Squassina, Deborah C. Mash, Brian W. Kunkle, Makrina Daniilidou, Alison Goate, David Carrell, Kara L. Hamilton-Nelson, Sandra Barral, Vincent Chouraki, Kristel Sleegers, Frank J. Wolters, Joseph E. Parisi, Iwona Kłoszewska, Ronald C. Kim, Sonia Moreno-Grau, Marina Arcaro, Carmen Muñoz Fernadez, Vernon S. Pankratz, Duane Beekly, Sabrina Pichler, Gislain Septier, Delphine Bacq, Amanda J. Myers, Adam C. Naj, Frank Martiniuk, Sudha Seshadri, Badri N. Vardarajan, Joshua A. Sonnen, M.-Marsel Mesulam, Howard J. Rosen, James T. Becker, Chiara Fenoglio, Ge Li, Alberto Pilotto, Mary Sano, Olivier Hanon, Honghuang Lin, Jean Paul G. Vonsattel, W. T. Longstreth, Daniela Galimberti, David C. Rubinsztein, RoseMarie Brundin, Vilmantas Giedraitis, Christine M. Hulette, Peter Holmans, Martin Dichgans, Maria Vronskaya, Céline Derbois, Michelangelo Mancuso, Constantine G. Lyketsos, Christophe Tzourio, Jacques Epelbaum, Raffaele Maletta, Mariet Allen, Hong-Dong Li, James R. Burke, Rik Vandenberghe, David G. Mann, Bruce M. Psaty, Lawrence S. Honig, Beth A. Dombroski, Erik D. Roberson, Cornelia M. van Duijn, Benjamin Grenier-Boley, Seppo Helisalmi, Jean-François Dartigues, Russell H. Swerdlow, Paola Bossù, Ashley R. Winslow, Elio Scarpini, Lesley Jones, Sebastien Engelborghs, John Q. Trojanowski, Jeffrey Kaye, Jenny Lord, Chiara Cupidi, Janet A. Johnston, Dan Rujescu, Feroze Golamaully, Anne Braae, Rafael Blesa, L. Adrienne Cupples, Dennis W. Dickson, Gail P. Jarvik, David W. Fardo, David H. Cribbs, Michael Gill, Jose Bras, Allan I. Levey, Jennifer Williamson, Rhodri Thomas, John C. Morris, Lei Yu, Debby W. Tsuang, Annette M. Hartmann, John H. Growdon, John Collinge, Claudine Berr, Fernando Rivadeneira, Oliver Peters, Albert Hofman, Frank M. LaFerla, Vivianna M. Van Deerlin, James Uphill, David A. Bennett, Onofre Combarros, Gudny Eiriksdottir, Jeremy D. Burgess, Melanie L. Dunstan, Elizabeth Crocco, Keeley J. Brookes, Robert R. Graham, Lon S. Schneider, Eden R. Martin, Matt Hill, Neill R. Graff-Radford, Joseph T. Hughes, Vincenzo Solfrizzi, Taniesha Morgan, Antonio Ciaramella, Bruno Dubois, Juan C. Troncoso, Paolo Bosco, Jordi Clarimón, Daniel H. Geschwind, Virginia Boccardi, Barry Reisberg, Timothy W. Behrens, Annette L. Fitzpatrick, Salvatore Spina, Alexis Brice, Eileen H. Bigio, Marla Gearing, Jeffrey M. Burns, Carol A. Miller, Marilyn S. Albert, Sven J. van der Lee, Sandro Sorbi, C. Dirk Keene, Daniel Levy, Antonio Daniele, Eric M. Reiman, Paramita Chakrabarty, Oscar Sotolongo-Grau, Helena Schmidt, Francesco Panza, Murray A. Raskind, Rita Guerreiro, Gyungah Jun, Anna Karydas, Markus Leber, Harry V. Vinters, Cory C. Funk, Charles C. White, Jill R. Murrell, Sid E. O'Bryant, Nigel J. Cairns, Josée Dupuis, Ann C. McKee, Julie A. Schneider, Megan L. Grove, Malcolm B. Dick, Bradley F. Boeve, Jennifer A. Brody, Sanjay Asthana, Agustín Ruiz, Stefan Herms, Yuning Chen, David Craig, Neil W. Kowall, Maria Donata Orfei, JoAnn T. Tschanz, Florentino Sanchez Garcia, Manuel Mayhaus, Alfredo Ramirez, James Turton, André G. Uitterlinden, Davide Seripa, Lee-Way Jin, Kelley Faber, Maria C. Norton, Shuo Li, Steven H. Ferris, Steffi G. Riedel-Heller, Joshua C. Bis, Li-San Wang, Johannes Kornhuber, Peter Paul De Deyn, Martin R. Farlow, Randall L. Woltjer, Gary W. Beecham, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Hospital of the University of Pennsylvania (HUP), Perelman School of Medicine, University of Pennsylvania [Philadelphia]-University of Pennsylvania [Philadelphia], 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), Icelandic Heart Association [Kopavogur, Iceland] (IHA), John P. Hussman Institute for Human Genomics [Miami, FL, USA], University of Miami [Coral Gables], 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), Department of Medicine, University of Washington [Seattle], Dr. John T. Macdonald Foundation [Miami, FL, USA] (Department of Human Genetics), Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, 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, Droit et Santé, Department of Genomics [Bonn, Germany] (Institute of Human Genetics), University of Bonn-Institute of Human Genetics [Bonn, Germany], Department of Molecular Genetics, Institut Català de Neurociències Aplicades [Barcelona, Spain], Well Advanced Solutions, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], The University of Texas Health Science Center at Houston (UTHealth), Columbia University [New York], University of Eastern Finland, Life & Brain Center - Department of Genomics, Rheinische Friedrich-Wilhelms-Universität Bonn, Génétique, Reproduction et Développement (GReD), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), John P. Hussman Institute for Human Genomics, Neurobiologie de la Croissance et de la Senescence, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Emmy Noether Project (SFB 833), Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Boston University [Boston] (BU), Department of Genomics, Institute for Systems Biology [Seattle, WA, USA], Universitätsklinikum Bonn (UKB), Centre of Excellence for Robotic Vision [Canberra], Australian Research Council [Canberra] (ARC), Neuroscience and Mental Health Research Institute [Cardiff, UK] (School of Medicine), Boston University School of Medicine (BUSM), Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, University of Pennsylvania [Philadelphia], Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Department of Epidemiology and Biostatistics, ERASMUS, Hospital Universitario Doctor Negrín [Las Palmas de Gran Canaria, Spain], Department of Neurodegenerative Diseases, University of Mississippi Medical Center (UMMC), Pathology and Laboratory Medicine [Philadelphia, PA, USA] (Penn Neurodegeneration Genomics Center), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Bioinformatics, GlaxoSmithKline, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], University of Nottingham, UK (UON), University of Texas Health Science Center, Department of Neurobiology, Caring Sciences and Society (NVS), University of Bari Aldo Moro (UNIBA), Ageing Group, Centre for Public Health, Queen's University [Belfast] (QUB), Mayo Clinic [Jacksonville], Maurice Wohl Clinical Neuroscience Institut, King‘s College London, Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Casa Sollievo della Sofferenza [San Giovanni Rotondo] (IRCCS), Università degli Studi di Perugia (UNIPG), Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), CHU Rouen, Normandie Université (NU), Universidad Autonoma de Madrid (UAM), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Florida [Gainesville] (UF), University of Parma = Università degli studi di Parma [Parme, Italie], Center for Cognitive Disorders AUSL [Parma, Italy], School of Public Health [Boston], Uppsala University, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), National Institute on Aging [Bethesda, USA] (NIA), National Institutes of Health [Bethesda] (NIH), Xi'an Jiaotong University (Xjtu), Department of Public health and Caring Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden, Institute of Gerontology and Geriatrics, Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Geriatric Medicine and Metabolic Diseases, Departments of Nuclear Medicine, University Medical Centre Hamburg-Eppendorf [Hamburg, Germany], University of Texas Southwestern Medical Center [Dallas], University of Cologne, Laboratoire d'Etudes et de Recherche en Informatique d'Angers (LERIA), Université d'Angers (UA), Johns Hopkins University (JHU), Universität Leipzig [Leipzig], University of Iceland [Reykjavik], Metacohorts Consortium, Harvard School of Public Health, Catholic University of Rome, Medical University Graz, Baylor College of Medicine (BCM), Baylor University, University of North Texas Health Science Center [Fort Worth], Santa Lucia Foundation (IRCCS), Nextel S.A. [Bilbao], Massachusetts General Hospital [Boston], Department of Pathology and Laboratory Medicine and Indiana Alzheimer disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Joint Institute for the Study of the Atmosphere and Ocean (JISAO), Beijing University of Technology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Saul B. Korey Department of Neurology, Albert Einstein College of Medicine [New York]-Yeshiva University, Utah State University (USU), Fundació per la Recerca Biomèdica i Social Mútua Terrassa [Barcelona, Spain], Hospital Universitario Mutua de Terrassa, Département de neurologie [Montpellier], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Medical University of Łódź (MUL), University of Leicester, MRC Prion Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, University of Milan, Fondazione Istituto di Ricerca e Cura Carattere Scientifico [Rome], Università degli Studi di Roma Tor Vergata [Roma], Saarland University Hospital, Universitat Autònoma de Barcelona (UAB), Regional Neurogenetic Centre [Lamezia Terme, Italy] (CRN - ASP Catanzaro), Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Universidade do Porto, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Experimental and Clinical Pharmacology, St. James Hospital and Trinity College [Dublin, Ireland], School of Medicine [Dublin], Trinity College Dublin, University of Sheffield [Sheffield], Lancaster University, University of Michigan [Ann Arbor], University of Michigan System, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Wisconsin-Madison, Rush Alzheimer Disease Center [Chicago, IL, États-Unis], Rush University Medical Center [Chicago], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), School of Engineering [Cardiff], Department of Psychiatry [Pittsburgh], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), Northwestern University Feinberg School of Medicine, Mayo Clinic [Rochester], Swedish Medical Center [Seattle, WA, USA], University of California [San Francisco] (UCSF), University of California, Duke University [Durham], University of Kansas Medical Center [Lawrence], Laboratory of Molecular Neuropsychiatry, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Washington University in Saint Louis (WUSTL), University of South Florida [Tampa] (USF), Fred Hutchinson Cancer Research Center [Seattle] (FHCRC), Medical University of South Carolina [Charleston] (MUSC), University of Southern California (USC), Los Alamos National Laboratory (LANL), Centre de biologie du développement (CBD), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre de Biologie Intégrative (CBI), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Neurology Department, University of California, Davis (UCDavis-Neuro), University of California [Davis] (UC Davis), University of California [Irvine] (UCI), Mount Sinai Medical Center, Indiana State University, University of Alabama at Birmingham [ Birmingham] (UAB), University of Kentucky, New York University [New York] (NYU), NYU System (NYU), Department of Medical and Molecular Genetics, Department of Epidemiology and biostatistics, VU University Medical Center [Amsterdam], Emory University [Atlanta, GA], Department of Neurology, University of California-University of California-David Geffen School of Medicine [Los Angeles], Brigham & Women’s Hospital [Boston] (BWH), Harvard Medical School [Boston] (HMS), Department of Medical Genetics, HMNC Brain Health, Alzheimer Disease Research Laboratory, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Oregon Health and Science University [Portland] (OHSU), Cleveland Clinic, Laboratoire d'Informatique, Systèmes, Traitement de l'Information et de la Connaissance (LISTIC), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry]), Department of Psychiatry, School of Medicine-Johns Hopkins University and Johns Hopkins Bayview Medical Center, Douglas Mental Health University Institute [Montréal], McGill University = Université McGill [Montréal, Canada], Department of neurosciences, University of California [San Diego] (UC San Diego), Department of Physics and Astronomy [Fort Worth], Texas Christian University (TCU), Department of Computer Science [University of California, Davis], Indiana University System, Institute for Aging and Alzheimer’s Disease Research [Fort Worth] (IAADR), Department of Laboratory Medicine and Pathology, Mayo Clinic, Institute for Memory Impairments and Neurological Disorders [Irvine], University of Colorado Anschutz [Aurora], Tanz Center Research in Neurodegenerative Diseases [Toronto], University of Toronto, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Keck School of Medicine [Los Angeles], Indiana University [South Bend], Massachusetts General Hospital, Novartis Institutes for Biomedical Research [Cambridge, MA, USA], Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology, UCLA Medical Center-David Geffen School of Medicine [Los Angeles], University of California-University of California-University of California [Los Angeles] (UCLA), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Institut de Génomique d'Evry (IG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, University of Antwerp (UA), Institute Born-Bunge, Karolinska Institutet [Stockholm], Karolinska University Hospital [Stockholm], University of Kuopio, Centre Mémoire de Ressources et de Recherche [Lille-Bailleul] (CMRR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille], Laboratoire d'Analyse Génomique, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Inserm-U1167, Dpt Gériatrie [CHU Broca], 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), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 AMP), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Epidemiology, University of Washington, School of Medicine [Los Angeles], Albert Einstein College of Medicine [New York], IdiPAZ - Instituto de Investigación La Paz [Madrid, Spain], Instituto de Física Teórica UAM/CSIC (IFT), Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Department of Internal Medicine, University of Central Asturias [Oviedo, Spain], Human Genome Sequencing Center, Baylor College of Medicine, Baylor University-Baylor University, Department of Epidemiology, Erasmus Medical Centre, Translational Genomics Research Institute [Phoenix, AZ, USA], University of Arizona, Banner Alzheimer's Institute [Phoenix, AZ, États-Unis], University of Texas Health Science Center at San Antonio [San Antonio], Mount Sinai School of Medicine, Department of Psychiatry-Icahn School of Medicine at Mount Sinai [New York] (MSSM), Department. of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico, Centre for Research in Neurodegenerative Diseases, VA Puget Sound Health Care System/GRECC [Seattle, WA, USA], University of Pisa - Università di Pisa, Pfizer Worldwide Research and Development [Cambridge, MA, USA], Università cattolica del Sacro Cuore [Piacenza e Cremona] (Unicatt), Texas Tech University Health Sciences Center, Texas Tech University [Lubbock] (TTU), Saarland University [Saarbrücken], University of Bonn, Department of Public Health and Primary Care, University of Cambridge [UK] (CAM), Cambridge Institute for Medical Research (CIMR), Department of Molecular Neurosciences, Institute of Neurology, UCL, Institute of Psychiatry, Institute of psychiatry, University of British Columbia (UBC), the Clinical Neuroscience Research Group, University of Manchester [Manchester]-Greater Manchester Neurosciences Centre, Aristotle University of Thessaloniki, Memory and Dementia Centre, 3rd Department of Neurology, G. Pa, University of Barcelona, University of Southampton, Department of Psychiatry [Oxford] (POWIC), University of Oxford [Oxford]-The Warneford Hospital, School of Psychology [Cardiff University], Department of Medical Sciences, UCL, Institute of Neurology [London], Washington University School of Medicine, Netherlands Genomics Initiative, Netherlands Consortium for Healthy Aging [Leiden, Netherlands] (NCHA), School of Medecine, Center for Translational and Computational Neuroimmunology [New York, NY, États-Unis] (CTCN), Department of Neurology [New York, NY, États-Unis], Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York]-Columbia University Medical Center (CUMC), Columbia University [New York]-Columbia University [New York], School of Life Sciences, Department of Neuroscience, Mayo Clinic Jacksonville, Icelandic Heart Association, Heart Preventive Clinic and Research Institute, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), The Center for Applied Genomics, Children’s Hospital of Philadelphia (CHOP ), Clínica Universidad de Navarra [Pamplona], Neurodegenerative Brain Diseases Group, VIB, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University-Medical Research Council, Brigham Young University (BYU), Institut de Santé Publique, d'Epidémiologie et de Développement (ISPED), Université Bordeaux Segalen - Bordeaux 2, The Gertrude H Sergivesky Center, Columbia University College of Physicians and Surgeons, Genetic Epidemiology Unit, Section of Clinical and Molecular Neurogenetics, Universität zu Lübeck [Lübeck], University of Pennsylvania - Department of Pathology & Laboratory Medecine, Framingham Heart Study [Framingham, MA, USA], ANR-10-IAHU-0006,IHU-A-ICM,Institut de Neurosciences Translationnelles de Paris(2010), European Project: 29845,LSH-ACC-MENTOR, University of Pennsylvania-University of Pennsylvania, Universität Bonn = University of Bonn-Institute of Human Genetics [Bonn, Germany], Universität Leipzig-Universität Leipzig, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania, Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Università degli Studi di Perugia = University of Perugia (UNIPG), Universidad Autónoma de Madrid (UAM), Università degli studi di Parma = University of Parma (UNIPR), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Universität Leipzig, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Yeshiva University- Albert Einstein College of Medicine [New York], Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université de Montpellier (UM), Università degli Studi di Milano = University of Milan (UNIMI), Saarland University Hospital (UKS), Università degli Studi di Firenze = University of Florence (UniFI), Universidade do Porto = University of Porto, University of California (UC)-University of California (UC), University of California [San Francisco] (UC San Francisco), University of California (UC), University of Kansas Medical Center [Kansas City, KS, USA], Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), University of California [Irvine] (UC Irvine), University of Kentucky (UK), University of California (UC)-University of California (UC)-David Geffen School of Medicine [Los Angeles], Department of Computer Science [Univ California Davis] (CS - UC Davis), University of California (UC)-University of California (UC)-University of California [Los Angeles] (UCLA), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Groupe de recherche clinique Alzheimer Precision Medicine (GRC 21 - APM), Sorbonne Université (SU), Universidad Autónoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), University of Texas Health Science Center at San Antonio [San Antonio, Tx, USA], Universität Bonn = University of Bonn, University of Oxford-The Warneford Hospital, Medical Research Council-Cardiff University, Universität zu Lübeck = University of Lübeck [Lübeck], Epidemiology, Neurology, Gastroenterology & Hepatology, Internal Medicine, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Eberhard Karls Universität Tübingen, IRCCS 'Casa Sollievo della Sofferenza', Centro de Investigación Biomédica en Red para Enfermedades Neurodegenerativas (Ciberned), University of Florida [Gainesville], University of Parma, Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Yeshiva University- Albert Einstein College of Medicine, Institut d’Électronique, de Microélectronique et de Nanotechnologie (IEMN) - UMR 8520 (IEMN), Centre National de la Recherche Scientifique (CNRS)-Université de Lille-Université Polytechnique Hauts-de-France (UPHF)-Ecole Centrale de Lille-Université Polytechnique Hauts-de-France (UPHF)-Institut supérieur de l'électronique et du numérique (ISEN), Autonomous University of Barcelona (UAB), Università degli Studi di Firenze [Firenze], Universidade do Porto [Porto], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Washington University in St Louis, University of South Florida (USF), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, McGill University, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Neuropsychiatrie : recherche épidémiologique et clinique, Alzheimer Precision Medicine GRC n°21 (APM), CHU Pitié-Salpêtrière [APHP], Albert Einstein College of Medicine, Universidad Autonoma de Madrid (UAM)-Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Università Cattolica del S. Cuore - Catholic University of the Sacred Hearth, University of Florence (UNIFI), CIBER de Enfermedades Neurodegenerativas (CIBERNED), Universität zu Lübeck [Lübeck] - University of Lübeck [Lübeck], [ANR-10-IAIHU-06],« Investissements d'avenir » ,Agence nationale de la recherche (ANR), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), 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)-CHU Pitié-Salpêtrière [AP-HP], Icahn School of Medicine at Mount Sinai [New York] (MSSM)-Department of Psychiatry, van der Lee, Sven J [0000-0003-1606-8643], Naj, Adam C [0000-0002-9621-2942], Badarinarayan, Nandini [0000-0002-6944-748X], Chouraki, Vincent [0000-0002-4698-1794], Graham, Robert R [0000-0001-7151-4277], Hoffmann, Per [0000-0002-6573-983X], Smith, Albert V [0000-0003-1942-5845], Satizabal, Claudia L [0000-0002-1115-4430], Brody, Jennifer A [0000-0001-8509-148X], Wolters, Frank J [0000-0003-2226-4050], Lupton, Michelle K [0000-0002-7274-7299], Lin, Honghuang [0000-0003-3043-3942], Adams, Hieab H [0000-0003-3687-2508], Giedraitis, Vilmantas [0000-0003-3423-2021], Pasquier, Florence [0000-0001-9880-9788], Chen, Yuning [0000-0002-7358-7055], Bossù, Paola [0000-0002-1432-0078], Ghetti, Bernardino [0000-0002-1842-8019], Yang, Qiong [0000-0002-3658-1375], Aspelund, Thor [0000-0002-7998-5433], Bullido, María J [0000-0002-6477-1117], Rivadeneira, Fernando [0000-0001-9435-9441], Rubinsztein, David C [0000-0001-5002-5263], Al-Chalabi, Ammar [0000-0002-4924-7712], Tsolaki, Magda [0000-0002-2072-8010], De Jager, Philip L [0000-0002-8057-2505], Dickson, Dennis W [0000-0001-7189-7917], Van Broeckhoven, Christine [0000-0003-0183-7665], Ikram, M Arfan [0000-0003-0372-8585], Amouyel, Philippe [0000-0001-9088-234X], Lambert, Jean-Charles [0000-0003-0829-7817], Apollo - University of Cambridge Repository, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI), Alzheimer Precision Medicine [CHU Pitié-Salpétriêre] (GRC 21 APM), Berr, Claudine, Institut de Neurosciences Translationnelles de Paris - - IHU-A-ICM2010 - ANR-10-IAHU-0006 - IAHU - VALID, and Mentoring of LifeSciHealth-Multipliers in the Accession Candidate Countries - LSH-ACC-MENTOR - 29845 - OLD
Subjects: 0301 basic medicine, Linkage disequilibrium, [SDV]Life Sciences [q-bio], Medizin, Sequence Homology, Genome-wide association study, genetics [Alzheimer Disease], metabolism [Microglia], Linkage Disequilibrium, 0302 clinical medicine, genetics [Protein Interaction Maps], genetics [Membrane Glycoproteins], Gene Frequency, Immunologic, genetics [Adaptor Proteins, Signal Transducing], Receptors, genetics [Exome], Odds Ratio, Innate, genetics [Receptors, Immunologic], Exome, Protein Interaction Maps, genetics [Genetic Predisposition to Disease], Receptors, Immunologic, ABI3 protein, human, Genetics, Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Membrane Glycoproteins, Microglia, Phospholipase C gamma, Sequence Homology, Amino Acid, Polymorphism, Single Nucleotide, Adaptor Proteins, Single Nucleotide, 3. Good health, [SDV] Life Sciences [q-bio], Amino Acid, Settore MED/26 - NEUROLOGIA, genetics [Phospholipase C gamma], [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Common disease-common variant, Biology, Article, 03 medical and health sciences, ddc:570, medicine, Journal Article, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Polymorphism, Allele frequency, TREM2 protein, human, TREM2, Case-control study, Signal Transducing, Immunity, medicine.disease, R1, Minor allele frequency, genetics [Immunity, Innate], 030104 developmental biology, Human medicine, 030217 neurology & neurosurgery
Abstract: International audience; We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.
Published: 2017
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48. Genetic Architecture of Subcortical Brain Structures in Over 40,000 Individuals Worldwide

Author: Arvin Saremi, Tomas Axelsson, Kristel R. van Eijk, Tonya White, Elena Shumskaya, Christine Macare, Christopher Chen, Neeltje E.M. van Haren, K Hegenscheid, Ingrid Melle, Benjamin S. Aribisala, Clyde Francks, Lisa R. Yanek, Konstantinos Arfanakis, Lars Nyberg, Nina Romanczuk-Seiferth, Clifford R. Jack, Thomas H. Wassink, Norman Delanty, Oscar L. Lopez, Jennifer S. Richards, Philippe Amouyel, William T. Longstreth, Michael W. Weiner, Maria J. Knol, Ralph Burkhardt, Ching-Yu Cheng, Wolfgang Hoffmann, Norbert Hosten, Alexander Teumer, Simone Reppermund, Markus M. Nöthen, Tien Yin Wong, Maria del C. Valdés Hernández, Bernd Kraemer, Murali Sargurupremraj, Amelia A. Assareh, Jessika E. Sussmann, Gabriel Cuellar-Partida, Ian J. Deary, Ganesh Chauhan, Christopher R.K. Ching, Arno Villringer, Dalia Kasperaviciute, Han G. Brunner, Srdjan Djurovic, Lachlan T. Strike, Albert V. Smith, Lars T. Westlye, Paul A. Nyquist, Bertram Müller-Myhsok, Phil Lee, Qiong Yang, Herve Lemaitre, Andreas Meyer-Lindenberg, Vidar M. Steen, Marc M. Bohlken, Rachel M. Brouwer, Charles DeCarli, Mar Matarin, Fabrice Crivello, Henry Völzke, Manuel Mattheisen, Bruno Vellas, Loes M. Olde Loohuis, Sudha Seshadri, Claudia L. Satizabal, Sebastian Mohnke, David C. Liewald, Li Shen, Kwangsik Nho, Simon E. Fisher, Deborah Janowitz, Wiro J. Niessen, Matthew J. Huentelman, Sylvane Desrivières, Ole A. Andreassen, Evan Fletcher, Christiane Wolf, Vilmundur Gudnason, Alejandro Arias-Vasquez, Charles C. White, Joshua C. Bis, Pauline Maillard, Ingrid Agartz, Oliver Grimm, Matthias Nauck, Andrew M. McIntosh, Iryna O. Fedko, Gianpiero L. Cavalleri, Andreas Heinz, Tulio Guadalupe, Andrew D. Johnson, Daan van Rooij, Thomas W. Mühleisen, Jessica A. Turner, Marieke Klein, Jia Yu Koh, Avram J. Holmes, Saud Alhusaini, Douglas N. Greve, Roberto Roiz-Santiañez, Nic J.A. van der Wee, Irina Filippi, Hans van Bokhoven, Miguel E. Rentería, Andrew J. Saykin, Marjolein M.J. van Donkelaar, Dan J. Stein, Randy L. Gollub, Sanjay M. Sisodiya, Honghuang Lin, Aaron Goldman, Patrizia Mecocci, Thomas Espeseth, Barbara Franke, Unn K. Haukvik, Theo G.M. van Erp, Venkata S. Mattay, Jonathan C Ipser, Catharina A. Hartman, Florian Holsboer, Saskia P. Hagenaars, Benedicto Crespo-Facorro, Manon Bernard, Jerome I. Rotter, Louis N. Vinke, Nastassja Koen, Vince D. Calhoun, Anders M. Dale, Dennis van der Meer, Jordan W. Smoller, Debra A. Fleischman, Janita Bralten, Hannah J. Jones, Lavinia Athanasiu, Hilleke E. Hulshoff Pol, Brenda W.J.H. Penninx, Peter R. Schofield, Roel A. Ophoff, J Wardlaw, Sven J. van der Lee, Katie L. McMahon, Esther Walton, Nicholas G. Martin, Gunter Schumann, Katharina Wittfeld, Perminder S. Sachdev, André G. Uitterlinden, Christophe Tzourio, Pieter J. Hoekstra, Roberto Toro, Henry Brodaty, Marcella Rietschel, David Ames, George Davey Smith, G. Bruce Pike, Alexa S. Beiser, Zdenka Pausova, Simon Lovestone, Robert C. Green, Greig I. de Zubicaray, Stephen M. Lawrie, Mark E. Bastin, Marco P. Boks, M. Mallar Chakravarty, Magda Tsolaki, Myriam Fornage, Nanda Rommelse, Andre F. Marquand, Anbupalam Thalamuthu, Helena Schmidt, Jason L. Stein, Bruce M. Psaty, Jan K. Buitelaar, Jean-Luc Martinot, Kazima B. Bulayeva, Henrik Walter, Xueqiu Jian, Yasaman Saba, Saima Hilal, Paul M. Thompson, Tamara B. Harris, Jaap Oosterlaan, Marie-José van Tol, Joshua L. Roffman, Bernard Mazoyer, Shuo Li, Nhat Trung Doan, Qiang Chen, John B.J. Kwok, Najaf Amin, Diana Tordesillas-Gutiérrez, Eco J. C. de Geus, Meike W. Vernooij, Andrew J. Schork, Susanne Erk, Daniel R. Weinberger, Grant W. Montgomery, Jean Shin, James T. Becker, Martine Hoogman, Philip L. De Jager, Dirk J. Heslenfeld, Derrek P. Hibar, Narelle K. Hansell, Andrew Simmons, Micael Andersson, Lucija Abramovic, Dorret I. Boomsma, Allison Stevens, Wei Wen, A. Veronica Witte, Owen Carmichael, Jayandra J. Himali, Asta Håberg, Hieab H.H. Adams, Nynke A. Groenewold, Sven Cichon, Wiepke Cahn, Lianne Schmaal, Shannon L. Risacher, Erik G. Jönsson, Shahrzad Kharabian Masouleh, Oliver Gruber, Tianye Jia, Hilkka Soininen, M. Kamran Ikram, Markus Loeffler, Philipp G. Sämann, Sungeun Kim, Jingyun Yang, Iwona Kłoszewska, Ryota Kanai, Christopher D. Whelan, Massimo Pandolfo, Dick J. Veltman, Diane M. Becker, Anouk den Braber, Hans J. Grabe, Neda Jahanshad, Yanhui Hu, Anita L. DeStefano, Beng-Choon Ho, Stephanie Le Hellard, Cornelia M. van Duijn, Georg Homuth, Tomáš Paus, Stéphanie Debette, Nicola J. Armstrong, Jouke-Jan Hottenga, Eric Westman, Tom V. Lee, Sarah E. Medland, Randy L. Buckner, Benno Pütz, Edith Hofer, Steven G. Potkin, Albert Hofman, Dennis van 't Ent, Sudheer Giddaluru, Tatiana Foroud, Guillén Fernández, John D. Eicher, Gareth E. Davies, Thomas H. Mosley, Michelle Luciano, Lenore J. Launer, Joshua W. Cheung, Markus Scholz, D. Höhn, Thomas Wolfers, Reinhold Schmidt, Arthur W. Toga, René S. Kahn, Nazanin Karbalai, Yuri Milaneschi, Margaret J. Wright, Martina Papmeyer, David A. Bennett, M. Arfan Ikram, Stefan Ehrlich, Marcel P. Zwiers, Karen A. Mather, and Joshua M. Shulman
Subjects: Candidate gene, Globus pallidus, nervous system, Putamen, Thalamus, Caudate nucleus, Synaptic signaling, Nucleus accumbens, Biology, Bioinformatics, Neuroscience, Genetic architecture
Abstract: Subcortical brain structures are integral to motion, consciousness, emotions, and learning. We identified common genetic variation related to the volumes of nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen, and thalamus, using genome-wide association analyses in over 40,000 individuals from CHARGE, ENIGMA and the UK-Biobank. We show that variability in subcortical volumes is heritable, and identify 25 significantly associated loci (20 novel). Annotation of these loci utilizing gene expression, methylation, and neuropathological data identified 62 candidate genes implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
Published: 2017
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49. [P3–090]: THE ALZHEIMER's DISEASE SEQUENCING PROJECT (ADSP) DATA UPDATE 2017

Author: Rebecca Cweibel, Elizabeth L. Appelbaum, John J. Farrell, Robert S. Fulton, Otto Valladares, Sudha Seshadri, Eric Boerwinkle, Laura B. Cantwell, Tatiana Foroud, Adam C. Naj, Seung Hoan Choi, Namrata Gupta, Liming Qu, Jason Waligorski, Mike Feolo, Gerard D. Schellenberg, Kara L. Hamilton-Nelson, Yuk Yee Leung, Amanda B. Kuzma, Anita L. DeStefano, Han-Jen Lin, Adam Stine, Dolly Reyes-Dumeyer, William J Salerno, Donna M. Muzny, Joshua C. Bis, Li-San Wang, and Kelley Faber
Subjects: Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, business.industry, Health Policy, Medicine, Neurology (clinical), Computational biology, Disease, Geriatrics and Gerontology, business
Published: 2017
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50. [O1–11–04]: TOPMED WHOLE GENOME SEQUENCE (WGS) ASSOCIATIONS WITH BRAIN MRI MEASURES IN THE FRAMINGHAM STUDY

Author: Sudha Seshadri, Alexa S. Beiser, Charles DeCarli, Anita L. DeStefano, Josée Dupuis, Achilleas N. Pitsillides, Chloé Sarnowski, and Claudia L. Satizabal
Subjects: Genetics, Whole genome sequencing, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Framingham Heart Study, Developmental Neuroscience, Epidemiology, Health Policy, Brain mri, Neurology (clinical), Geriatrics and Gerontology, Biology
Published: 2017
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