학술논문
Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
Document Type
Original Paper
Author
de Rojas, Itziar; Moreno-Grau, Sonia; Tesi, Niccolo; Grenier-Boley, Benjamin; Andrade, Victor; Jansen, Iris E.; Pedersen, Nancy L.; Stringa, Najada; Zettergren, Anna; Hernández, Isabel; Montrreal, Laura; Antúnez, Carmen; Antonell, Anna; Tankard, Rick M.; Bis, Joshua C.; Sims, Rebecca; Bellenguez, Céline; Quintela, Inés; González-Perez, Antonio; Calero, Miguel; Franco-Macías, Emilio; Macías, Juan; Blesa, Rafael; Cervera-Carles, Laura; Menéndez-González, Manuel; Frank-García, Ana; Royo, Jose Luís; Moreno, Fermin; Huerto Vilas, Raquel; Baquero, Miquel; Diez-Fairen, Mónica; Lage, Carmen; García-Madrona, Sebastián; García-González, Pablo; Alarcón-Martín, Emilio; Valero, Sergi; Sotolongo-Grau, Oscar; Ullgren, Abbe; Naj, Adam C.; Lemstra, Afina W.; Benaque, Alba; Pérez-Cordón, Alba; Benussi, Alberto; Rábano, Alberto; Padovani, Alessandro; Squassina, Alessio; de Mendonça, Alexandre; Arias Pastor, Alfonso; Kok, Almar A. L.; Meggy, Alun; Pastor, Ana Belén; Espinosa, Ana; Corma-Gómez, Anaïs; Martín Montes, Angel; Sanabria, Ángela; DeStefano, Anita L.; Schneider, Anja; Haapasalo, Annakaisa; Kinhult Ståhlbom, Anne; Tybjærg-Hansen, Anne; Hartmann, Annette M.; Spottke, Annika; Corbatón-Anchuelo, Arturo; Rongve, Arvid; Borroni, Barbara; Arosio, Beatrice; Nacmias, Benedetta; Nordestgaard, Børge G.; Kunkle, Brian W.; Charbonnier, Camille; Abdelnour, Carla; Masullo, Carlo; Martínez Rodríguez, Carmen; Muñoz-Fernandez, Carmen; Dufouil, Carole; Graff, Caroline; Ferreira, Catarina B.; Chillotti, Caterina; Reynolds, Chandra A.; Fenoglio, Chiara; Van Broeckhoven, Christine; Clark, Christopher; Pisanu, Claudia; Satizabal, Claudia L.; Holmes, Clive; Buiza-Rueda, Dolores; Aarsland, Dag; Rujescu, Dan; Alcolea, Daniel; Galimberti, Daniela; Wallon, David; Seripa, Davide; Grünblatt, Edna; Dardiotis, Efthimios; Düzel, Emrah; Scarpini, Elio; Conti, Elisa; Rubino, Elisa; Gelpi, Ellen; Rodriguez-Rodriguez, Eloy; Duron, Emmanuelle; Boerwinkle, Eric; Ferri, Evelyn; Tagliavini, Fabrizio; Küçükali, Fahri; Pasquier, Florence; Sanchez-Garcia, Florentino; Mangialasche, Francesca; Jessen, Frank; Nicolas, Gaël; Selbæk, Geir; Ortega, Gemma; Chêne, Geneviève; Hadjigeorgiou, Georgios; Rossi, Giacomina; Spalletta, Gianfranco; Giaccone, Giorgio; Grande, Giulia; Binetti, Giuliano; Papenberg, Goran; Hampel, Harald; Bailly, Henri; Zetterberg, Henrik; Soininen, Hilkka; Karlsson, Ida K.; Alvarez, Ignacio; Appollonio, Ildebrando; Giegling, Ina; Skoog, Ingmar; Saltvedt, Ingvild; Rainero, Innocenzo; Rosas Allende, Irene; Hort, Jakub; Diehl-Schmid, Janine; Van Dongen, Jasper; Vidal, Jean-Sebastien; Lehtisalo, Jenni; Wiltfang, Jens; Thomassen, Jesper Qvist; Kornhuber, Johannes; Haines, Jonathan L.; Vogelgsang, Jonathan; Pineda, Juan A.; Fortea, Juan; Popp, Julius; Deckert, Jürgen; Buerger, Katharina; Morgan, Kevin; Fließbach, Klaus; Sleegers, Kristel; Molina-Porcel, Laura; Kilander, Lena; Weinhold, Leonie; Farrer, Lindsay A.; Wang, Li-San; Kleineidam, Luca; Farotti, Lucia; Parnetti, Lucilla; Tremolizzo, Lucio; Hausner, Lucrezia; Benussi, Luisa; Froelich, Lutz; Ikram, M. Arfan; Deniz-Naranjo, M. Candida; Tsolaki, Magda; Rosende-Roca, Maitée; Löwenmark, Malin; Hulsman, Marc; Spallazzi, Marco; Pericak-Vance, Margaret A.; Esiri, Margaret; Bernal Sánchez-Arjona, María; Dalmasso, Maria Carolina; Martínez-Larrad, María Teresa; Arcaro, Marina; Nöthen, Markus M.; Fernández-Fuertes, Marta; Dichgans, Martin; Ingelsson, Martin; Herrmann, Martin J.; Scherer, Martin; Vyhnalek, Martin; Kosmidis, Mary H.; Yannakoulia, Mary; Schmid, Matthias; Ewers, Michael; Heneka, Michael T.; Wagner, Michael; Scamosci, Michela; Kivipelto, Miia; Hiltunen, Mikko; Zulaica, Miren; Alegret, Montserrat; Fornage, Myriam; Roberto, Natalia; van Schoor, Natasja M.; Seidu, Nazib M.; Banaj, Nerisa; Armstrong, Nicola J.; Scarmeas, Nikolaos; Scherbaum, Norbert; Goldhardt, Oliver; Hanon, Oliver; Peters, Oliver; Skrobot, Olivia Anna; Quenez, Olivier; Lerch, Ondrej; Bossù, Paola; Caffarra, Paolo; Dionigi Rossi, Paolo; Sakka, Paraskevi; Mecocci, Patrizia; Hoffmann, Per; Holmans, Peter A.; Fischer, Peter; Riederer, Peter; Yang, Qiong; Marshall, Rachel; Kalaria, Rajesh N.; Mayeux, Richard; Vandenberghe, Rik; Cecchetti, Roberta; Ghidoni, Roberta; Frikke-Schmidt, Ruth; Sorbi, Sandro; Hägg, Sara; Engelborghs, Sebastiaan; Helisalmi, Seppo; Botne Sando, Sigrid; Kern, Silke; Archetti, Silvana; Boschi, Silvia; Fostinelli, Silvia; Gil, Silvia; Mendoza, Silvia; Mead, Simon; Ciccone, Simona; Djurovic, Srdjan; Heilmann-Heimbach, Stefanie; Riedel-Heller, Steffi; Kuulasmaa, Teemu; del Ser, Teodoro; Lebouvier, Thibaud; Polak, Thomas; Ngandu, Tiia; Grimmer, Timo; Bessi, Valentina; Escott-Price, Valentina; Giedraitis, Vilmantas; Deramecourt, Vincent; Maier, Wolfgang; Jian, Xueqiu; Pijnenburg, Yolande A. L.; Kehoe, Patrick Gavin; Garcia-Ribas, Guillermo; Sánchez-Juan, Pascual; Pastor, Pau; Pérez-Tur, Jordi; Piñol-Ripoll, Gerard; Lopez de Munain, Adolfo; García-Alberca, Jose María; Bullido, María J.; Álvarez, Victoria; Lleó, Alberto; Real, Luis M.; Mir, Pablo; Medina, Miguel; Scheltens, Philip; Holstege, Henne; Marquié, Marta; Sáez, María Eugenia; Carracedo, Ángel; Amouyel, Philippe; Schellenberg, Gerard D.; Williams, Julie; Seshadri, Sudha; van Duijn, Cornelia M.; Mather, Karen A.; Sánchez-Valle, Raquel; Serrano-Ríos, Manuel; Orellana, Adelina; Tárraga, Lluís; Blennow, Kaj; Huisman, Martijn; Andreassen, Ole A.; Posthuma, Danielle; Clarimón, Jordi; Boada, Mercè; van der Flier, Wiesje M.; Ramirez, Alfredo; Lambert, Jean-Charles; van der Lee, Sven J.; Ruiz, Agustín
Source
Nature Communications. 12(1)
Subject
Language
English
ISSN
2041-1723
Abstract
Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease.
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.
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.