Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
Itziar de Rojas, Sonia Moreno–Grau, Niccoló Tesi, Benjamin Grenier‐Boley, Víctor 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-Pérez, Miguel Calero, Emilio Franco‐Macías, Juan Macı́as, Rafael Blesa, Laura Cervera‐Carles, Manuel Menéndez‐González, Ana Frank, José Luís Royo, Fermín Moreno, Raquel Huerto Vilas, Miquel Baquero, Mónica Díez-Fairén, Carmen Lage, Sebastián García‐Madrona, Pablo García‐González, Emilio Alarcón‐Martín, Sergi Valero, Óscar 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, Ángel 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-Fernández, Carole Dufouil, Caroline Graff, Catarina B. Ferreira, Caterina Chillotti, Chandra A. Reynolds, Chiara Fenoglio, Christine Van Broeckhoven, Christopher Clark, Claudia Pisanu, Claudia L. Satizábal, 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 Gelpí, Eloy Rodríguez‐Rodríguez
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.