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Frank-García AAuthorBullido, Maria JAuthor

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Common variants in Alzheimer's disease and risk stratification by polygenic risk scores

Publicated to:Nature Communications. 12 (1): 3417- - 2021-06-07 12(1), DOI: 10.1038/s41467-021-22491-8

Authors: de Rojas, Itziar; Moreno-Grau, Sonia; Tesi, Niccolo; Grenier-Boley, Benjamin; Andrade, Victor; Jansen, Iris E; Pedersen, Nancy L; Stringa, Najada; Zettergren, Anna; Hernandez, Isabel; Montrreal, Laura; Antunez, Carmen; Antonell, Anna; Tankard, Rick M; Bis, Joshua C; Sims, Rebecca; Bellenguez, Celine; Quintela, Ines; Gonzalez-Perez, Antonio; Calero, Miguel; Franco-Macias, Emilio; Macias, Juan; Blesa, Rafael; Cervera-Carles, Laura; Menendez-Gonzalez, Manuel; Frank-Garcia, Ana; Luis Royo, Jose; Moreno, Fermin; Huerto Vilas, Raquel; Baquero, Miquel; Diez-Fairen, Monica; Lage, Carmen; Garcia-Madrona, Sebastian; Garcia-Gonzalez, Pablo; Alarcon-Martin, Emilio; Valero, Sergi; Sotolongo-Grau, Oscar; Ullgren, Abbe; Naj, Adam C; Lemstra, Afina W; Benaque, Alba; Perez-Cordon, Alba; Benussi, Alberto; Rabano, Alberto; Padovani, Alessandro; Squassina, Alessio; de Mendonca, Alexandre; Arias Pastor, Alfonso; Kok, Almar A L; Meggy, Alun; Belen Pastor, Ana; Espinosa, Ana; Corma-Gomez, Anais; Martin Montes, Angel; Sanabria, Angela; DeStefano, Anita L; Schneider, Anja; Haapasalo, Annakaisa; Stahlbom, Anne Kinhult; Tybjaerg-Hansen, Anne; Hartmann, Annette M; Spottke, Annika; Corbaton-Anchuelo, Arturo; Rongve, Arvid; Borroni, Barbara; Arosio, Beatrice; Nacmias, Benedetta; Nordestgaard, Borge G; Kunkle, Brian W; Charbonnier, Camille; Abdelnour, Carla; Masullo, Carlo; Martinez Rodriguez, Carmen; Munoz-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; Gruenblatt, Edna; Dardiotis, Efthimios; Duezel, Emrah; Scarpini, Elio; Conti, Elisa; Rubino, Elisa; Gelpi, Ellen; Rodriguez-Rodriguez, Eloy; Duron, Emmanuelle; Boerwinkle, Eric; Ferri, Evelyn; Tagliavini, Fabrizio; Kucukali, Fahri; Pasquier, Florence; Sanchez-Garcia, Florentino; Mangialasche, Francesca; Jessen, Frank; Nicolas, Gael; Selbaek, Geir; Ortega, Gemma; Chene, Genevieve; 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; Allende, Irene Rosas; 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, Juergen; 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, Maitee; Lowenmark, Malin; Hulsman, Marc; Spallazzi, Marco; Pericak-Vance, Margaret A; Esiri, Margaret; Sanchez-Arjona, Maria Bernal; Carolina Dalmasso, Maria; Teresa Martinez-Larrad, Maria; Arcaro, Marina; Noethen, Markus M; Fernandez-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; Bossu, Paola; Caffarra, Paolo; Rossi, Paolo Dionigi; Sakka, Paraskevi; 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; Hagg, Sara; Engelborghs, Sebastiaan; Helisalmi, Seppo; Sando, Sigrid Botne; 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; Sanchez-Juan, Pascual; Pastor, Pau; Perez-Tur, Jordi; Pinol-Ripoll, Gerard; de Munain, Adolfo Lopez; Maria Garcia-Alberca, Jose; Bullido, Maria J; Alvarez, Victoria; Lleo, Alberto; Real, Luis M; Mir, Pablo; Medina, Miguel; Scheltens, Philip; Holstege, Henne; Marquie, Marta; Eugenia Saez, Maria; Carracedo, Angel; Amouyel, Philippe; Schellenberg, Gerard D; Williams, Julie; Seshadri, Sudha; van Duijn, Cornelia M; Mather, Karen A; Sanchez-Valle, Raquel; Serrano-Rios, Manuel; Orellana, Adelina; Tarraga, Lluis; Blennow, Kaj; Huisman, Martijn; Andreassen, Ole A; Posthuma, Danielle; Clarimon, Jordi; Boada, Merce; van der Flier, Wiesje M; Ramirez, Alfredo; Lambert, Jean-Charles; van der Lee, Sven J; Ruiz, Agustin

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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.

Keywords