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New insights into the genetic etiology of Alzheimer’s disease and related dementias
Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘pro...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group US
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005347/ https://www.ncbi.nlm.nih.gov/pubmed/35379992 http://dx.doi.org/10.1038/s41588-022-01024-z |
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author | Bellenguez, Céline Küçükali, Fahri Jansen, Iris E. Kleineidam, Luca Moreno-Grau, Sonia Amin, Najaf Naj, Adam C. Campos-Martin, Rafael Grenier-Boley, Benjamin Andrade, Victor Holmans, Peter A. Boland, Anne Damotte, Vincent van der Lee, Sven J. Costa, Marcos R. Kuulasmaa, Teemu Yang, Qiong de Rojas, Itziar Bis, Joshua C. Yaqub, Amber Prokic, Ivana Chapuis, Julien Ahmad, Shahzad Giedraitis, Vilmantas Aarsland, Dag Garcia-Gonzalez, Pablo Abdelnour, Carla Alarcón-Martín, Emilio Alcolea, Daniel Alegret, Montserrat Alvarez, Ignacio Álvarez, Victoria Armstrong, Nicola J. Tsolaki, Anthoula Antúnez, Carmen Appollonio, Ildebrando Arcaro, Marina Archetti, Silvana Pastor, Alfonso Arias Arosio, Beatrice Athanasiu, Lavinia Bailly, Henri Banaj, Nerisa Baquero, Miquel Barral, Sandra Beiser, Alexa Pastor, Ana Belén Below, Jennifer E. Benchek, Penelope Benussi, Luisa Berr, Claudine Besse, Céline Bessi, Valentina Binetti, Giuliano Bizarro, Alessandra Blesa, Rafael Boada, Mercè Boerwinkle, Eric Borroni, Barbara Boschi, Silvia Bossù, Paola Bråthen, Geir Bressler, Jan Bresner, Catherine Brodaty, Henry Brookes, Keeley J. Brusco, Luis Ignacio Buiza-Rueda, Dolores Bûrger, Katharina Burholt, Vanessa Bush, William S. Calero, Miguel Cantwell, Laura B. Chene, Geneviève Chung, Jaeyoon Cuccaro, Michael L. Carracedo, Ángel Cecchetti, Roberta Cervera-Carles, Laura Charbonnier, Camille Chen, Hung-Hsin Chillotti, Caterina Ciccone, Simona Claassen, Jurgen A. H. R. Clark, Christopher Conti, Elisa Corma-Gómez, Anaïs Costantini, Emanuele Custodero, Carlo Daian, Delphine Dalmasso, Maria Carolina Daniele, Antonio Dardiotis, Efthimios Dartigues, Jean-François de Deyn, Peter Paul de Paiva Lopes, Katia de Witte, Lot D. Debette, Stéphanie Deckert, Jürgen del Ser, Teodoro Denning, Nicola DeStefano, Anita Dichgans, Martin Diehl-Schmid, Janine Diez-Fairen, Mónica Rossi, Paolo Dionigi Djurovic, Srdjan Duron, Emmanuelle Düzel, Emrah Dufouil, Carole Eiriksdottir, Gudny Engelborghs, Sebastiaan Escott-Price, Valentina Espinosa, Ana Ewers, Michael Faber, Kelley M. Fabrizio, Tagliavini Nielsen, Sune Fallgaard Fardo, David W. Farotti, Lucia Fenoglio, Chiara Fernández-Fuertes, Marta Ferrari, Raffaele Ferreira, Catarina B. Ferri, Evelyn Fin, Bertrand Fischer, Peter Fladby, Tormod Fließbach, Klaus Fongang, Bernard Fornage, Myriam Fortea, Juan Foroud, Tatiana M. Fostinelli, Silvia Fox, Nick C. Franco-Macías, Emlio Bullido, María J. Frank-García, Ana Froelich, Lutz Fulton-Howard, Brian Galimberti, Daniela García-Alberca, Jose Maria García-González, Pablo Garcia-Madrona, Sebastian Garcia-Ribas, Guillermo Ghidoni, Roberta Giegling, Ina Giorgio, Giaccone Goate, Alison M. Goldhardt, Oliver Gomez-Fonseca, Duber González-Pérez, Antonio Graff, Caroline Grande, Giulia Green, Emma Grimmer, Timo Grünblatt, Edna Grunin, Michelle Gudnason, Vilmundur Guetta-Baranes, Tamar Haapasalo, Annakaisa Hadjigeorgiou, Georgios Haines, Jonathan L. Hamilton-Nelson, Kara L. Hampel, Harald Hanon, Olivier Hardy, John Hartmann, Annette M. Hausner, Lucrezia Harwood, Janet Heilmann-Heimbach, Stefanie Helisalmi, Seppo Heneka, Michael T. Hernández, Isabel Herrmann, Martin J. Hoffmann, Per Holmes, Clive Holstege, Henne Vilas, Raquel Huerto Hulsman, Marc Humphrey, Jack Biessels, Geert Jan Jian, Xueqiu Johansson, Charlotte Jun, Gyungah R. Kastumata, Yuriko Kauwe, John Kehoe, Patrick G. Kilander, Lena Ståhlbom, Anne Kinhult Kivipelto, Miia Koivisto, Anne Kornhuber, Johannes Kosmidis, Mary H. Kukull, Walter A. Kuksa, Pavel P. Kunkle, Brian W. Kuzma, Amanda B. Lage, Carmen Laukka, Erika J. Launer, Lenore Lauria, Alessandra Lee, Chien-Yueh Lehtisalo, Jenni Lerch, Ondrej Lleó, Alberto Longstreth, William Lopez, Oscar de Munain, Adolfo Lopez Love, Seth Löwemark, Malin Luckcuck, Lauren Lunetta, Kathryn L. Ma, Yiyi Macías, Juan MacLeod, Catherine A. Maier, Wolfgang Mangialasche, Francesca Spallazzi, Marco Marquié, Marta Marshall, Rachel Martin, Eden R. Montes, Angel Martín Rodríguez, Carmen Martínez Masullo, Carlo Mayeux, Richard Mead, Simon Mecocci, Patrizia Medina, Miguel Meggy, Alun Mehrabian, Shima Mendoza, Silvia Menéndez-González, Manuel Mir, Pablo Moebus, Susanne Mol, Merel Molina-Porcel, Laura Montrreal, Laura Morelli, Laura Moreno, Fermin Morgan, Kevin Mosley, Thomas Nöthen, Markus M. Muchnik, Carolina Mukherjee, Shubhabrata Nacmias, Benedetta Ngandu, Tiia Nicolas, Gael Nordestgaard, Børge G. Olaso, Robert Orellana, Adelina Orsini, Michela Ortega, Gemma Padovani, Alessandro Paolo, Caffarra Papenberg, Goran Parnetti, Lucilla Pasquier, Florence Pastor, Pau Peloso, Gina Pérez-Cordón, Alba Pérez-Tur, Jordi Pericard, Pierre Peters, Oliver Pijnenburg, Yolande A. L. Pineda, Juan A. Piñol-Ripoll, Gerard Pisanu, Claudia Polak, Thomas Popp, Julius Posthuma, Danielle Priller, Josef Puerta, Raquel Quenez, Olivier Quintela, Inés Thomassen, Jesper Qvist Rábano, Alberto Rainero, Innocenzo Rajabli, Farid Ramakers, Inez Real, Luis M. Reinders, Marcel J. T. Reitz, Christiane Reyes-Dumeyer, Dolly Ridge, Perry Riedel-Heller, Steffi Riederer, Peter Roberto, Natalia Rodriguez-Rodriguez, Eloy Rongve, Arvid Allende, Irene Rosas Rosende-Roca, Maitée Royo, Jose Luis Rubino, Elisa Rujescu, Dan Sáez, María Eugenia Sakka, Paraskevi Saltvedt, Ingvild Sanabria, Ángela Sánchez-Arjona, María Bernal Sanchez-Garcia, Florentino Juan, Pascual Sánchez Sánchez-Valle, Raquel Sando, Sigrid B. Sarnowski, Chloé Satizabal, Claudia L. Scamosci, Michela Scarmeas, Nikolaos Scarpini, Elio Scheltens, Philip Scherbaum, Norbert Scherer, Martin Schmid, Matthias Schneider, Anja Schott, Jonathan M. Selbæk, Geir Seripa, Davide Serrano, Manuel Sha, Jin Shadrin, Alexey A. Skrobot, Olivia Slifer, Susan Snijders, Gijsje J. L. Soininen, Hilkka Solfrizzi, Vincenzo Solomon, Alina Song, Yeunjoo Sorbi, Sandro Sotolongo-Grau, Oscar Spalletta, Gianfranco Spottke, Annika Squassina, Alessio Stordal, Eystein Tartan, Juan Pablo Tárraga, Lluís Tesí, Niccolo Thalamuthu, Anbupalam Thomas, Tegos Tosto, Giuseppe Traykov, Latchezar Tremolizzo, Lucio Tybjærg-Hansen, Anne Uitterlinden, Andre Ullgren, Abbe Ulstein, Ingun Valero, Sergi Valladares, Otto Broeckhoven, Christine Van Vance, Jeffery Vardarajan, Badri N. van der Lugt, Aad Dongen, Jasper Van van Rooij, Jeroen van Swieten, John Vandenberghe, Rik Verhey, Frans Vidal, Jean-Sébastien Vogelgsang, Jonathan Vyhnalek, Martin Wagner, Michael Wallon, David Wang, Li-San Wang, Ruiqi Weinhold, Leonie Wiltfang, Jens Windle, Gill Woods, Bob Yannakoulia, Mary Zare, Habil Zhao, Yi Zhang, Xiaoling Zhu, Congcong Zulaica, Miren Farrer, Lindsay A. Psaty, Bruce M. Ghanbari, Mohsen Raj, Towfique Sachdev, Perminder Mather, Karen Jessen, Frank Ikram, M. Arfan de Mendonça, Alexandre Hort, Jakub Tsolaki, Magda Pericak-Vance, Margaret A. Amouyel, Philippe Williams, Julie Frikke-Schmidt, Ruth Clarimon, Jordi Deleuze, Jean-François Rossi, Giacomina Seshadri, Sudha Andreassen, Ole A. Ingelsson, Martin Hiltunen, Mikko Sleegers, Kristel Schellenberg, Gerard D. van Duijn, Cornelia M. Sims, Rebecca van der Flier, Wiesje M. Ruiz, Agustín Ramirez, Alfredo Lambert, Jean-Charles |
author_facet | Bellenguez, Céline Küçükali, Fahri Jansen, Iris E. Kleineidam, Luca Moreno-Grau, Sonia Amin, Najaf Naj, Adam C. Campos-Martin, Rafael Grenier-Boley, Benjamin Andrade, Victor Holmans, Peter A. Boland, Anne Damotte, Vincent van der Lee, Sven J. Costa, Marcos R. Kuulasmaa, Teemu Yang, Qiong de Rojas, Itziar Bis, Joshua C. Yaqub, Amber Prokic, Ivana Chapuis, Julien Ahmad, Shahzad Giedraitis, Vilmantas Aarsland, Dag Garcia-Gonzalez, Pablo Abdelnour, Carla Alarcón-Martín, Emilio Alcolea, Daniel Alegret, Montserrat Alvarez, Ignacio Álvarez, Victoria Armstrong, Nicola J. Tsolaki, Anthoula Antúnez, Carmen Appollonio, Ildebrando Arcaro, Marina Archetti, Silvana Pastor, Alfonso Arias Arosio, Beatrice Athanasiu, Lavinia Bailly, Henri Banaj, Nerisa Baquero, Miquel Barral, Sandra Beiser, Alexa Pastor, Ana Belén Below, Jennifer E. Benchek, Penelope Benussi, Luisa Berr, Claudine Besse, Céline Bessi, Valentina Binetti, Giuliano Bizarro, Alessandra Blesa, Rafael Boada, Mercè Boerwinkle, Eric Borroni, Barbara Boschi, Silvia Bossù, Paola Bråthen, Geir Bressler, Jan Bresner, Catherine Brodaty, Henry Brookes, Keeley J. Brusco, Luis Ignacio Buiza-Rueda, Dolores Bûrger, Katharina Burholt, Vanessa Bush, William S. Calero, Miguel Cantwell, Laura B. Chene, Geneviève Chung, Jaeyoon Cuccaro, Michael L. Carracedo, Ángel Cecchetti, Roberta Cervera-Carles, Laura Charbonnier, Camille Chen, Hung-Hsin Chillotti, Caterina Ciccone, Simona Claassen, Jurgen A. H. R. Clark, Christopher Conti, Elisa Corma-Gómez, Anaïs Costantini, Emanuele Custodero, Carlo Daian, Delphine Dalmasso, Maria Carolina Daniele, Antonio Dardiotis, Efthimios Dartigues, Jean-François de Deyn, Peter Paul de Paiva Lopes, Katia de Witte, Lot D. Debette, Stéphanie Deckert, Jürgen del Ser, Teodoro Denning, Nicola DeStefano, Anita Dichgans, Martin Diehl-Schmid, Janine Diez-Fairen, Mónica Rossi, Paolo Dionigi Djurovic, Srdjan Duron, Emmanuelle Düzel, Emrah Dufouil, Carole Eiriksdottir, Gudny Engelborghs, Sebastiaan Escott-Price, Valentina Espinosa, Ana Ewers, Michael Faber, Kelley M. Fabrizio, Tagliavini Nielsen, Sune Fallgaard Fardo, David W. Farotti, Lucia Fenoglio, Chiara Fernández-Fuertes, Marta Ferrari, Raffaele Ferreira, Catarina B. Ferri, Evelyn Fin, Bertrand Fischer, Peter Fladby, Tormod Fließbach, Klaus Fongang, Bernard Fornage, Myriam Fortea, Juan Foroud, Tatiana M. Fostinelli, Silvia Fox, Nick C. Franco-Macías, Emlio Bullido, María J. Frank-García, Ana Froelich, Lutz Fulton-Howard, Brian Galimberti, Daniela García-Alberca, Jose Maria García-González, Pablo Garcia-Madrona, Sebastian Garcia-Ribas, Guillermo Ghidoni, Roberta Giegling, Ina Giorgio, Giaccone Goate, Alison M. Goldhardt, Oliver Gomez-Fonseca, Duber González-Pérez, Antonio Graff, Caroline Grande, Giulia Green, Emma Grimmer, Timo Grünblatt, Edna Grunin, Michelle Gudnason, Vilmundur Guetta-Baranes, Tamar Haapasalo, Annakaisa Hadjigeorgiou, Georgios Haines, Jonathan L. Hamilton-Nelson, Kara L. Hampel, Harald Hanon, Olivier Hardy, John Hartmann, Annette M. Hausner, Lucrezia Harwood, Janet Heilmann-Heimbach, Stefanie Helisalmi, Seppo Heneka, Michael T. Hernández, Isabel Herrmann, Martin J. Hoffmann, Per Holmes, Clive Holstege, Henne Vilas, Raquel Huerto Hulsman, Marc Humphrey, Jack Biessels, Geert Jan Jian, Xueqiu Johansson, Charlotte Jun, Gyungah R. Kastumata, Yuriko Kauwe, John Kehoe, Patrick G. Kilander, Lena Ståhlbom, Anne Kinhult Kivipelto, Miia Koivisto, Anne Kornhuber, Johannes Kosmidis, Mary H. Kukull, Walter A. Kuksa, Pavel P. Kunkle, Brian W. Kuzma, Amanda B. Lage, Carmen Laukka, Erika J. Launer, Lenore Lauria, Alessandra Lee, Chien-Yueh Lehtisalo, Jenni Lerch, Ondrej Lleó, Alberto Longstreth, William Lopez, Oscar de Munain, Adolfo Lopez Love, Seth Löwemark, Malin Luckcuck, Lauren Lunetta, Kathryn L. Ma, Yiyi Macías, Juan MacLeod, Catherine A. Maier, Wolfgang Mangialasche, Francesca Spallazzi, Marco Marquié, Marta Marshall, Rachel Martin, Eden R. Montes, Angel Martín Rodríguez, Carmen Martínez Masullo, Carlo Mayeux, Richard Mead, Simon Mecocci, Patrizia Medina, Miguel Meggy, Alun Mehrabian, Shima Mendoza, Silvia Menéndez-González, Manuel Mir, Pablo Moebus, Susanne Mol, Merel Molina-Porcel, Laura Montrreal, Laura Morelli, Laura Moreno, Fermin Morgan, Kevin Mosley, Thomas Nöthen, Markus M. Muchnik, Carolina Mukherjee, Shubhabrata Nacmias, Benedetta Ngandu, Tiia Nicolas, Gael Nordestgaard, Børge G. Olaso, Robert Orellana, Adelina Orsini, Michela Ortega, Gemma Padovani, Alessandro Paolo, Caffarra Papenberg, Goran Parnetti, Lucilla Pasquier, Florence Pastor, Pau Peloso, Gina Pérez-Cordón, Alba Pérez-Tur, Jordi Pericard, Pierre Peters, Oliver Pijnenburg, Yolande A. L. Pineda, Juan A. Piñol-Ripoll, Gerard Pisanu, Claudia Polak, Thomas Popp, Julius Posthuma, Danielle Priller, Josef Puerta, Raquel Quenez, Olivier Quintela, Inés Thomassen, Jesper Qvist Rábano, Alberto Rainero, Innocenzo Rajabli, Farid Ramakers, Inez Real, Luis M. Reinders, Marcel J. T. Reitz, Christiane Reyes-Dumeyer, Dolly Ridge, Perry Riedel-Heller, Steffi Riederer, Peter Roberto, Natalia Rodriguez-Rodriguez, Eloy Rongve, Arvid Allende, Irene Rosas Rosende-Roca, Maitée Royo, Jose Luis Rubino, Elisa Rujescu, Dan Sáez, María Eugenia Sakka, Paraskevi Saltvedt, Ingvild Sanabria, Ángela Sánchez-Arjona, María Bernal Sanchez-Garcia, Florentino Juan, Pascual Sánchez Sánchez-Valle, Raquel Sando, Sigrid B. Sarnowski, Chloé Satizabal, Claudia L. Scamosci, Michela Scarmeas, Nikolaos Scarpini, Elio Scheltens, Philip Scherbaum, Norbert Scherer, Martin Schmid, Matthias Schneider, Anja Schott, Jonathan M. Selbæk, Geir Seripa, Davide Serrano, Manuel Sha, Jin Shadrin, Alexey A. Skrobot, Olivia Slifer, Susan Snijders, Gijsje J. L. Soininen, Hilkka Solfrizzi, Vincenzo Solomon, Alina Song, Yeunjoo Sorbi, Sandro Sotolongo-Grau, Oscar Spalletta, Gianfranco Spottke, Annika Squassina, Alessio Stordal, Eystein Tartan, Juan Pablo Tárraga, Lluís Tesí, Niccolo Thalamuthu, Anbupalam Thomas, Tegos Tosto, Giuseppe Traykov, Latchezar Tremolizzo, Lucio Tybjærg-Hansen, Anne Uitterlinden, Andre Ullgren, Abbe Ulstein, Ingun Valero, Sergi Valladares, Otto Broeckhoven, Christine Van Vance, Jeffery Vardarajan, Badri N. van der Lugt, Aad Dongen, Jasper Van van Rooij, Jeroen van Swieten, John Vandenberghe, Rik Verhey, Frans Vidal, Jean-Sébastien Vogelgsang, Jonathan Vyhnalek, Martin Wagner, Michael Wallon, David Wang, Li-San Wang, Ruiqi Weinhold, Leonie Wiltfang, Jens Windle, Gill Woods, Bob Yannakoulia, Mary Zare, Habil Zhao, Yi Zhang, Xiaoling Zhu, Congcong Zulaica, Miren Farrer, Lindsay A. Psaty, Bruce M. Ghanbari, Mohsen Raj, Towfique Sachdev, Perminder Mather, Karen Jessen, Frank Ikram, M. Arfan de Mendonça, Alexandre Hort, Jakub Tsolaki, Magda Pericak-Vance, Margaret A. Amouyel, Philippe Williams, Julie Frikke-Schmidt, Ruth Clarimon, Jordi Deleuze, Jean-François Rossi, Giacomina Seshadri, Sudha Andreassen, Ole A. Ingelsson, Martin Hiltunen, Mikko Sleegers, Kristel Schellenberg, Gerard D. van Duijn, Cornelia M. Sims, Rebecca van der Flier, Wiesje M. Ruiz, Agustín Ramirez, Alfredo Lambert, Jean-Charles |
author_sort | Bellenguez, Céline |
collection | PubMed |
description | Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. |
format | Online Article Text |
id | pubmed-9005347 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group US |
record_format | MEDLINE/PubMed |
spelling | pubmed-90053472022-04-27 New insights into the genetic etiology of Alzheimer’s disease and related dementias Bellenguez, Céline Küçükali, Fahri Jansen, Iris E. Kleineidam, Luca Moreno-Grau, Sonia Amin, Najaf Naj, Adam C. Campos-Martin, Rafael Grenier-Boley, Benjamin Andrade, Victor Holmans, Peter A. Boland, Anne Damotte, Vincent van der Lee, Sven J. Costa, Marcos R. Kuulasmaa, Teemu Yang, Qiong de Rojas, Itziar Bis, Joshua C. Yaqub, Amber Prokic, Ivana Chapuis, Julien Ahmad, Shahzad Giedraitis, Vilmantas Aarsland, Dag Garcia-Gonzalez, Pablo Abdelnour, Carla Alarcón-Martín, Emilio Alcolea, Daniel Alegret, Montserrat Alvarez, Ignacio Álvarez, Victoria Armstrong, Nicola J. Tsolaki, Anthoula Antúnez, Carmen Appollonio, Ildebrando Arcaro, Marina Archetti, Silvana Pastor, Alfonso Arias Arosio, Beatrice Athanasiu, Lavinia Bailly, Henri Banaj, Nerisa Baquero, Miquel Barral, Sandra Beiser, Alexa Pastor, Ana Belén Below, Jennifer E. Benchek, Penelope Benussi, Luisa Berr, Claudine Besse, Céline Bessi, Valentina Binetti, Giuliano Bizarro, Alessandra Blesa, Rafael Boada, Mercè Boerwinkle, Eric Borroni, Barbara Boschi, Silvia Bossù, Paola Bråthen, Geir Bressler, Jan Bresner, Catherine Brodaty, Henry Brookes, Keeley J. Brusco, Luis Ignacio Buiza-Rueda, Dolores Bûrger, Katharina Burholt, Vanessa Bush, William S. Calero, Miguel Cantwell, Laura B. Chene, Geneviève Chung, Jaeyoon Cuccaro, Michael L. Carracedo, Ángel Cecchetti, Roberta Cervera-Carles, Laura Charbonnier, Camille Chen, Hung-Hsin Chillotti, Caterina Ciccone, Simona Claassen, Jurgen A. H. R. Clark, Christopher Conti, Elisa Corma-Gómez, Anaïs Costantini, Emanuele Custodero, Carlo Daian, Delphine Dalmasso, Maria Carolina Daniele, Antonio Dardiotis, Efthimios Dartigues, Jean-François de Deyn, Peter Paul de Paiva Lopes, Katia de Witte, Lot D. Debette, Stéphanie Deckert, Jürgen del Ser, Teodoro Denning, Nicola DeStefano, Anita Dichgans, Martin Diehl-Schmid, Janine Diez-Fairen, Mónica Rossi, Paolo Dionigi Djurovic, Srdjan Duron, Emmanuelle Düzel, Emrah Dufouil, Carole Eiriksdottir, Gudny Engelborghs, Sebastiaan Escott-Price, Valentina Espinosa, Ana Ewers, Michael Faber, Kelley M. Fabrizio, Tagliavini Nielsen, Sune Fallgaard Fardo, David W. Farotti, Lucia Fenoglio, Chiara Fernández-Fuertes, Marta Ferrari, Raffaele Ferreira, Catarina B. Ferri, Evelyn Fin, Bertrand Fischer, Peter Fladby, Tormod Fließbach, Klaus Fongang, Bernard Fornage, Myriam Fortea, Juan Foroud, Tatiana M. Fostinelli, Silvia Fox, Nick C. Franco-Macías, Emlio Bullido, María J. Frank-García, Ana Froelich, Lutz Fulton-Howard, Brian Galimberti, Daniela García-Alberca, Jose Maria García-González, Pablo Garcia-Madrona, Sebastian Garcia-Ribas, Guillermo Ghidoni, Roberta Giegling, Ina Giorgio, Giaccone Goate, Alison M. Goldhardt, Oliver Gomez-Fonseca, Duber González-Pérez, Antonio Graff, Caroline Grande, Giulia Green, Emma Grimmer, Timo Grünblatt, Edna Grunin, Michelle Gudnason, Vilmundur Guetta-Baranes, Tamar Haapasalo, Annakaisa Hadjigeorgiou, Georgios Haines, Jonathan L. Hamilton-Nelson, Kara L. Hampel, Harald Hanon, Olivier Hardy, John Hartmann, Annette M. Hausner, Lucrezia Harwood, Janet Heilmann-Heimbach, Stefanie Helisalmi, Seppo Heneka, Michael T. Hernández, Isabel Herrmann, Martin J. Hoffmann, Per Holmes, Clive Holstege, Henne Vilas, Raquel Huerto Hulsman, Marc Humphrey, Jack Biessels, Geert Jan Jian, Xueqiu Johansson, Charlotte Jun, Gyungah R. Kastumata, Yuriko Kauwe, John Kehoe, Patrick G. Kilander, Lena Ståhlbom, Anne Kinhult Kivipelto, Miia Koivisto, Anne Kornhuber, Johannes Kosmidis, Mary H. Kukull, Walter A. Kuksa, Pavel P. Kunkle, Brian W. Kuzma, Amanda B. Lage, Carmen Laukka, Erika J. Launer, Lenore Lauria, Alessandra Lee, Chien-Yueh Lehtisalo, Jenni Lerch, Ondrej Lleó, Alberto Longstreth, William Lopez, Oscar de Munain, Adolfo Lopez Love, Seth Löwemark, Malin Luckcuck, Lauren Lunetta, Kathryn L. Ma, Yiyi Macías, Juan MacLeod, Catherine A. Maier, Wolfgang Mangialasche, Francesca Spallazzi, Marco Marquié, Marta Marshall, Rachel Martin, Eden R. Montes, Angel Martín Rodríguez, Carmen Martínez Masullo, Carlo Mayeux, Richard Mead, Simon Mecocci, Patrizia Medina, Miguel Meggy, Alun Mehrabian, Shima Mendoza, Silvia Menéndez-González, Manuel Mir, Pablo Moebus, Susanne Mol, Merel Molina-Porcel, Laura Montrreal, Laura Morelli, Laura Moreno, Fermin Morgan, Kevin Mosley, Thomas Nöthen, Markus M. Muchnik, Carolina Mukherjee, Shubhabrata Nacmias, Benedetta Ngandu, Tiia Nicolas, Gael Nordestgaard, Børge G. Olaso, Robert Orellana, Adelina Orsini, Michela Ortega, Gemma Padovani, Alessandro Paolo, Caffarra Papenberg, Goran Parnetti, Lucilla Pasquier, Florence Pastor, Pau Peloso, Gina Pérez-Cordón, Alba Pérez-Tur, Jordi Pericard, Pierre Peters, Oliver Pijnenburg, Yolande A. L. Pineda, Juan A. Piñol-Ripoll, Gerard Pisanu, Claudia Polak, Thomas Popp, Julius Posthuma, Danielle Priller, Josef Puerta, Raquel Quenez, Olivier Quintela, Inés Thomassen, Jesper Qvist Rábano, Alberto Rainero, Innocenzo Rajabli, Farid Ramakers, Inez Real, Luis M. Reinders, Marcel J. T. Reitz, Christiane Reyes-Dumeyer, Dolly Ridge, Perry Riedel-Heller, Steffi Riederer, Peter Roberto, Natalia Rodriguez-Rodriguez, Eloy Rongve, Arvid Allende, Irene Rosas Rosende-Roca, Maitée Royo, Jose Luis Rubino, Elisa Rujescu, Dan Sáez, María Eugenia Sakka, Paraskevi Saltvedt, Ingvild Sanabria, Ángela Sánchez-Arjona, María Bernal Sanchez-Garcia, Florentino Juan, Pascual Sánchez Sánchez-Valle, Raquel Sando, Sigrid B. Sarnowski, Chloé Satizabal, Claudia L. Scamosci, Michela Scarmeas, Nikolaos Scarpini, Elio Scheltens, Philip Scherbaum, Norbert Scherer, Martin Schmid, Matthias Schneider, Anja Schott, Jonathan M. Selbæk, Geir Seripa, Davide Serrano, Manuel Sha, Jin Shadrin, Alexey A. Skrobot, Olivia Slifer, Susan Snijders, Gijsje J. L. Soininen, Hilkka Solfrizzi, Vincenzo Solomon, Alina Song, Yeunjoo Sorbi, Sandro Sotolongo-Grau, Oscar Spalletta, Gianfranco Spottke, Annika Squassina, Alessio Stordal, Eystein Tartan, Juan Pablo Tárraga, Lluís Tesí, Niccolo Thalamuthu, Anbupalam Thomas, Tegos Tosto, Giuseppe Traykov, Latchezar Tremolizzo, Lucio Tybjærg-Hansen, Anne Uitterlinden, Andre Ullgren, Abbe Ulstein, Ingun Valero, Sergi Valladares, Otto Broeckhoven, Christine Van Vance, Jeffery Vardarajan, Badri N. van der Lugt, Aad Dongen, Jasper Van van Rooij, Jeroen van Swieten, John Vandenberghe, Rik Verhey, Frans Vidal, Jean-Sébastien Vogelgsang, Jonathan Vyhnalek, Martin Wagner, Michael Wallon, David Wang, Li-San Wang, Ruiqi Weinhold, Leonie Wiltfang, Jens Windle, Gill Woods, Bob Yannakoulia, Mary Zare, Habil Zhao, Yi Zhang, Xiaoling Zhu, Congcong Zulaica, Miren Farrer, Lindsay A. Psaty, Bruce M. Ghanbari, Mohsen Raj, Towfique Sachdev, Perminder Mather, Karen Jessen, Frank Ikram, M. Arfan de Mendonça, Alexandre Hort, Jakub Tsolaki, Magda Pericak-Vance, Margaret A. Amouyel, Philippe Williams, Julie Frikke-Schmidt, Ruth Clarimon, Jordi Deleuze, Jean-François Rossi, Giacomina Seshadri, Sudha Andreassen, Ole A. Ingelsson, Martin Hiltunen, Mikko Sleegers, Kristel Schellenberg, Gerard D. van Duijn, Cornelia M. Sims, Rebecca van der Flier, Wiesje M. Ruiz, Agustín Ramirez, Alfredo Lambert, Jean-Charles Nat Genet Article Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. Nature Publishing Group US 2022-04-04 2022 /pmc/articles/PMC9005347/ /pubmed/35379992 http://dx.doi.org/10.1038/s41588-022-01024-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Bellenguez, Céline Küçükali, Fahri Jansen, Iris E. Kleineidam, Luca Moreno-Grau, Sonia Amin, Najaf Naj, Adam C. Campos-Martin, Rafael Grenier-Boley, Benjamin Andrade, Victor Holmans, Peter A. Boland, Anne Damotte, Vincent van der Lee, Sven J. Costa, Marcos R. Kuulasmaa, Teemu Yang, Qiong de Rojas, Itziar Bis, Joshua C. Yaqub, Amber Prokic, Ivana Chapuis, Julien Ahmad, Shahzad Giedraitis, Vilmantas Aarsland, Dag Garcia-Gonzalez, Pablo Abdelnour, Carla Alarcón-Martín, Emilio Alcolea, Daniel Alegret, Montserrat Alvarez, Ignacio Álvarez, Victoria Armstrong, Nicola J. Tsolaki, Anthoula Antúnez, Carmen Appollonio, Ildebrando Arcaro, Marina Archetti, Silvana Pastor, Alfonso Arias Arosio, Beatrice Athanasiu, Lavinia Bailly, Henri Banaj, Nerisa Baquero, Miquel Barral, Sandra Beiser, Alexa Pastor, Ana Belén Below, Jennifer E. Benchek, Penelope Benussi, Luisa Berr, Claudine Besse, Céline Bessi, Valentina Binetti, Giuliano Bizarro, Alessandra Blesa, Rafael Boada, Mercè Boerwinkle, Eric Borroni, Barbara Boschi, Silvia Bossù, Paola Bråthen, Geir Bressler, Jan Bresner, Catherine Brodaty, Henry Brookes, Keeley J. Brusco, Luis Ignacio Buiza-Rueda, Dolores Bûrger, Katharina Burholt, Vanessa Bush, William S. Calero, Miguel Cantwell, Laura B. Chene, Geneviève Chung, Jaeyoon Cuccaro, Michael L. Carracedo, Ángel Cecchetti, Roberta Cervera-Carles, Laura Charbonnier, Camille Chen, Hung-Hsin Chillotti, Caterina Ciccone, Simona Claassen, Jurgen A. H. R. Clark, Christopher Conti, Elisa Corma-Gómez, Anaïs Costantini, Emanuele Custodero, Carlo Daian, Delphine Dalmasso, Maria Carolina Daniele, Antonio Dardiotis, Efthimios Dartigues, Jean-François de Deyn, Peter Paul de Paiva Lopes, Katia de Witte, Lot D. Debette, Stéphanie Deckert, Jürgen del Ser, Teodoro Denning, Nicola DeStefano, Anita Dichgans, Martin Diehl-Schmid, Janine Diez-Fairen, Mónica Rossi, Paolo Dionigi Djurovic, Srdjan Duron, Emmanuelle Düzel, Emrah Dufouil, Carole Eiriksdottir, Gudny Engelborghs, Sebastiaan Escott-Price, Valentina Espinosa, Ana Ewers, Michael Faber, Kelley M. Fabrizio, Tagliavini Nielsen, Sune Fallgaard Fardo, David W. Farotti, Lucia Fenoglio, Chiara Fernández-Fuertes, Marta Ferrari, Raffaele Ferreira, Catarina B. Ferri, Evelyn Fin, Bertrand Fischer, Peter Fladby, Tormod Fließbach, Klaus Fongang, Bernard Fornage, Myriam Fortea, Juan Foroud, Tatiana M. Fostinelli, Silvia Fox, Nick C. Franco-Macías, Emlio Bullido, María J. Frank-García, Ana Froelich, Lutz Fulton-Howard, Brian Galimberti, Daniela García-Alberca, Jose Maria García-González, Pablo Garcia-Madrona, Sebastian Garcia-Ribas, Guillermo Ghidoni, Roberta Giegling, Ina Giorgio, Giaccone Goate, Alison M. Goldhardt, Oliver Gomez-Fonseca, Duber González-Pérez, Antonio Graff, Caroline Grande, Giulia Green, Emma Grimmer, Timo Grünblatt, Edna Grunin, Michelle Gudnason, Vilmundur Guetta-Baranes, Tamar Haapasalo, Annakaisa Hadjigeorgiou, Georgios Haines, Jonathan L. Hamilton-Nelson, Kara L. Hampel, Harald Hanon, Olivier Hardy, John Hartmann, Annette M. Hausner, Lucrezia Harwood, Janet Heilmann-Heimbach, Stefanie Helisalmi, Seppo Heneka, Michael T. Hernández, Isabel Herrmann, Martin J. Hoffmann, Per Holmes, Clive Holstege, Henne Vilas, Raquel Huerto Hulsman, Marc Humphrey, Jack Biessels, Geert Jan Jian, Xueqiu Johansson, Charlotte Jun, Gyungah R. Kastumata, Yuriko Kauwe, John Kehoe, Patrick G. Kilander, Lena Ståhlbom, Anne Kinhult Kivipelto, Miia Koivisto, Anne Kornhuber, Johannes Kosmidis, Mary H. Kukull, Walter A. Kuksa, Pavel P. Kunkle, Brian W. Kuzma, Amanda B. Lage, Carmen Laukka, Erika J. Launer, Lenore Lauria, Alessandra Lee, Chien-Yueh Lehtisalo, Jenni Lerch, Ondrej Lleó, Alberto Longstreth, William Lopez, Oscar de Munain, Adolfo Lopez Love, Seth Löwemark, Malin Luckcuck, Lauren Lunetta, Kathryn L. Ma, Yiyi Macías, Juan MacLeod, Catherine A. Maier, Wolfgang Mangialasche, Francesca Spallazzi, Marco Marquié, Marta Marshall, Rachel Martin, Eden R. Montes, Angel Martín Rodríguez, Carmen Martínez Masullo, Carlo Mayeux, Richard Mead, Simon Mecocci, Patrizia Medina, Miguel Meggy, Alun Mehrabian, Shima Mendoza, Silvia Menéndez-González, Manuel Mir, Pablo Moebus, Susanne Mol, Merel Molina-Porcel, Laura Montrreal, Laura Morelli, Laura Moreno, Fermin Morgan, Kevin Mosley, Thomas Nöthen, Markus M. Muchnik, Carolina Mukherjee, Shubhabrata Nacmias, Benedetta Ngandu, Tiia Nicolas, Gael Nordestgaard, Børge G. Olaso, Robert Orellana, Adelina Orsini, Michela Ortega, Gemma Padovani, Alessandro Paolo, Caffarra Papenberg, Goran Parnetti, Lucilla Pasquier, Florence Pastor, Pau Peloso, Gina Pérez-Cordón, Alba Pérez-Tur, Jordi Pericard, Pierre Peters, Oliver Pijnenburg, Yolande A. L. Pineda, Juan A. Piñol-Ripoll, Gerard Pisanu, Claudia Polak, Thomas Popp, Julius Posthuma, Danielle Priller, Josef Puerta, Raquel Quenez, Olivier Quintela, Inés Thomassen, Jesper Qvist Rábano, Alberto Rainero, Innocenzo Rajabli, Farid Ramakers, Inez Real, Luis M. Reinders, Marcel J. T. Reitz, Christiane Reyes-Dumeyer, Dolly Ridge, Perry Riedel-Heller, Steffi Riederer, Peter Roberto, Natalia Rodriguez-Rodriguez, Eloy Rongve, Arvid Allende, Irene Rosas Rosende-Roca, Maitée Royo, Jose Luis Rubino, Elisa Rujescu, Dan Sáez, María Eugenia Sakka, Paraskevi Saltvedt, Ingvild Sanabria, Ángela Sánchez-Arjona, María Bernal Sanchez-Garcia, Florentino Juan, Pascual Sánchez Sánchez-Valle, Raquel Sando, Sigrid B. Sarnowski, Chloé Satizabal, Claudia L. Scamosci, Michela Scarmeas, Nikolaos Scarpini, Elio Scheltens, Philip Scherbaum, Norbert Scherer, Martin Schmid, Matthias Schneider, Anja Schott, Jonathan M. Selbæk, Geir Seripa, Davide Serrano, Manuel Sha, Jin Shadrin, Alexey A. Skrobot, Olivia Slifer, Susan Snijders, Gijsje J. L. Soininen, Hilkka Solfrizzi, Vincenzo Solomon, Alina Song, Yeunjoo Sorbi, Sandro Sotolongo-Grau, Oscar Spalletta, Gianfranco Spottke, Annika Squassina, Alessio Stordal, Eystein Tartan, Juan Pablo Tárraga, Lluís Tesí, Niccolo Thalamuthu, Anbupalam Thomas, Tegos Tosto, Giuseppe Traykov, Latchezar Tremolizzo, Lucio Tybjærg-Hansen, Anne Uitterlinden, Andre Ullgren, Abbe Ulstein, Ingun Valero, Sergi Valladares, Otto Broeckhoven, Christine Van Vance, Jeffery Vardarajan, Badri N. van der Lugt, Aad Dongen, Jasper Van van Rooij, Jeroen van Swieten, John Vandenberghe, Rik Verhey, Frans Vidal, Jean-Sébastien Vogelgsang, Jonathan Vyhnalek, Martin Wagner, Michael Wallon, David Wang, Li-San Wang, Ruiqi Weinhold, Leonie Wiltfang, Jens Windle, Gill Woods, Bob Yannakoulia, Mary Zare, Habil Zhao, Yi Zhang, Xiaoling Zhu, Congcong Zulaica, Miren Farrer, Lindsay A. Psaty, Bruce M. Ghanbari, Mohsen Raj, Towfique Sachdev, Perminder Mather, Karen Jessen, Frank Ikram, M. Arfan de Mendonça, Alexandre Hort, Jakub Tsolaki, Magda Pericak-Vance, Margaret A. Amouyel, Philippe Williams, Julie Frikke-Schmidt, Ruth Clarimon, Jordi Deleuze, Jean-François Rossi, Giacomina Seshadri, Sudha Andreassen, Ole A. Ingelsson, Martin Hiltunen, Mikko Sleegers, Kristel Schellenberg, Gerard D. van Duijn, Cornelia M. Sims, Rebecca van der Flier, Wiesje M. Ruiz, Agustín Ramirez, Alfredo Lambert, Jean-Charles New insights into the genetic etiology of Alzheimer’s disease and related dementias |
title | New insights into the genetic etiology of Alzheimer’s disease and related dementias |
title_full | New insights into the genetic etiology of Alzheimer’s disease and related dementias |
title_fullStr | New insights into the genetic etiology of Alzheimer’s disease and related dementias |
title_full_unstemmed | New insights into the genetic etiology of Alzheimer’s disease and related dementias |
title_short | New insights into the genetic etiology of Alzheimer’s disease and related dementias |
title_sort | new insights into the genetic etiology of alzheimer’s disease and related dementias |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005347/ https://www.ncbi.nlm.nih.gov/pubmed/35379992 http://dx.doi.org/10.1038/s41588-022-01024-z |
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