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

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Item Type:Article
Title:Common variants in Alzheimer's disease and risk stratification by polygenic risk scores
Creators Name:de Rojas, I. and Moreno-Grau, S. and Tesi, N. and Grenier-Boley, B. and Andrade, V. and Jansen, I.E. and Pedersen, N.L. and Stringa, N. and Zettergren, A. and Hernández, I. and Montrreal, L. and Antúnez, C. and Antonell, A. and Tankard, R.M. and Bis, J.C. and Sims, R. and Bellenguez, C. and Quintela, I. and González-Perez, A. and Calero, M. and Franco-Macías, E. and Macías, J. and Blesa, R. and Cervera-Carles, L. and Menéndez-González, M. and Frank-García, A. and Royo, J.L. and Moreno, F. and Huerto Vilas, R. and Baquero, M. and Diez-Fairen, M. and Lage, C. and García-Madrona, S. and García-González, P. and Alarcón-Martín, E. and Valero, S. and Sotolongo-Grau, O. and Ullgren, A. and Naj, A.C. and Lemstra, A.W. and Benaque, A. and Pérez-Cordón, A. and Benussi, A. and Rábano, A. and Padovani, A. and Squassina, A. and de Mendonça, A. and Arias Pastor, A. and Kok, A.A.L. and Meggy, A. and Pastor, A.B. and Espinosa, A. and Corma-Gómez, A. and Martín Montes, A. and Sanabria, Á. and DeStefano, A.L. and Schneider, A. and Haapasalo, A. and Kinhult Ståhlbom, A. and Tybjærg-Hansen, A. and Hartmann, A.M. and Spottke, A. and Corbatón-Anchuelo, A. and Rongve, A. and Borroni, B. and Arosio, B. and Nacmias, B. and Nordestgaard, B.G. and Kunkle, B.W. and Charbonnier, C. and Abdelnour, C. and Masullo, C. and Martínez Rodríguez, C. and Muñoz-Fernandez, C. and Dufouil, C. and Graff, C. and Ferreira, C.B. and Chillotti, C. and Reynolds, C.A. and Fenoglio, C. and Van Broeckhoven, C. and Clark, C. and Pisanu, C. and Satizabal, C.L. and Holmes, C. and Buiza-Rueda, D. and Aarsland, D. and Rujescu, D. and Alcolea, D. and Galimberti, D. and Wallon, D. and Seripa, D. and Grünblatt, E. and Dardiotis, E. and Düzel, E. and Scarpini, E. and Conti, E. and Rubino, E. and Gelpi, E. and Rodriguez-Rodriguez, E. and Duron, E. and Boerwinkle, E. and Ferri, E. and Tagliavini, F. and Küçükali, F. and Pasquier, F. and Sanchez-Garcia, F. and Mangialasche, F. and Jessen, F. and Nicolas, G. and Selbæk, G. and Ortega, G. and Chêne, G. and Hadjigeorgiou, G. and Rossi, G. and Spalletta, G. and Giaccone, G. and Grande, G. and Binetti, G. and Papenberg, G. and Hampel, H. and Bailly, H. and Zetterberg, H. and Soininen, H. and Karlsson, I.K. and Alvarez, I. and Appollonio, I. and Giegling, I. and Skoog, I. and Saltvedt, I. and Rainero, I. and Rosas Allende, I. and Hort, J. and Diehl-Schmid, J. and Van Dongen, J. and Vidal, J.S. and Lehtisalo, J. and Wiltfang, J. and Thomassen, J.Q. and Kornhuber, J. and Haines, J.L. and Vogelgsang, J. and Pineda, J.A. and Fortea, J. and Popp, J. and Deckert, J. and Buerger, K. and Morgan, K. and Fließbach, K. and Sleegers, K. and Molina-Porcel, L. and Kilander, L. and Weinhold, L. and Farrer, L.A. and Wang, L.S. and Kleineidam, L. and Farotti, L. and Parnetti, L. and Tremolizzo, L. and Hausner, L. and Benussi, L. and Froelich, L. and Ikram, M.A. and Deniz-Naranjo, M.C. and Tsolaki, M. and Rosende-Roca, M. and Löwenmark, M. and Hulsman, M. and Spallazzi, M. and Pericak-Vance, M.A. and Esiri, M. and Bernal Sánchez-Arjona, M. and Dalmasso, M.C. and Martínez-Larrad, M.T. and Arcaro, M. and Nöthen, M.M. and Fernández-Fuertes, M. and Dichgans, M. and Ingelsson, M. and Herrmann, M.J. and Scherer, M. and Vyhnalek, M. and Kosmidis, M.H. and Yannakoulia, M. and Schmid, M. and Ewers, M. and Heneka, M.T. and Wagner, M. and Scamosci, M. and Kivipelto, M. and Hiltunen, M. and Zulaica, M. and Alegret, M. and Fornage, M. and Roberto, N. and van Schoor, N.M. and Seidu, N.M. and Banaj, N. and Armstrong, N.J. and Scarmeas, N. and Scherbaum, N. and Goldhardt, O. and Hanon, O. and Peters, O. and Skrobot, O.A. and Quenez, O. and Lerch, O. and Bossù, P. and Caffarra, P. and Dionigi Rossi, P. and Sakka, P. and Hoffmann, P. and Holmans, P.A. and Fischer, P. and Riederer, P. and Yang, Q. and Marshall, R. and Kalaria, R.N. and Mayeux, R. and Vandenberghe, R. and Cecchetti, R. and Ghidoni, R. and Frikke-Schmidt, R. and Sorbi, S. and Hägg, S. and Engelborghs, S. and Helisalmi, S. and Botne Sando, S. and Kern, S. and Archetti, S. and Boschi, S. and Fostinelli, S. and Gil, S. and Mendoza, S. and Mead, S. and Ciccone, S. and Djurovic, S. and Heilmann-Heimbach, S. and Riedel-Heller, S. and Kuulasmaa, T. and Del Ser, T. and Lebouvier, T. and Polak, T. and Ngandu, T. and Grimmer, T. and Bessi, V. and Escott-Price, V. and Giedraitis, V. and Deramecourt, Vi. and Maier, W. and Jian, X. and Pijnenburg, Y.A.L. and Kehoe, P.G. and Garcia-Ribas, G. and Sánchez-Juan, P. and Pastor, P. and Pérez-Tur, J. and Piñol-Ripoll, G. and Lopez de Munain, A. and García-Alberca, J.M. and Bullido, M.J. and Álvarez, V. and Lleó, A. and Real, L.M. and Mir, P. and Medina, M. and Scheltens, P. and Holstege, H. and Marquié, M. and Sáez, M.E. and Carracedo, Á. and Amouyel, P. and Schellenberg, G.D. and Williams, J. and Seshadri, S. and van Duijn, C.M. and Mather, K.A. and Sánchez-Valle, R. and Serrano-Ríos, M. and Orellana, A. and Tárraga, L. and Blennow, K. and Huisman, M. and Andreassen, O.A. and Posthuma, D. and Clarimón, J. and Boada, M. and van der Flier, W.M. and Ramirez, A. and Lambert, J.C. and van der Lee, S.J. and Ruiz, A.
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:Age of Onset, Alzheimer Disease, Amyloid beta-Protein Precursor, Apolipoproteins E, Case-Control Studies, Cohort Studies, Datasets As Topic, Follow-Up Studies, Genetic Predisposition To Disease, Genome-Wide Association Study, Heterozygote, Multifactorial Inheritance, Risk Assessment, Risk Factors, Single Nucleotide Polymorphism
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:3417
Date:7 June 2021
Official Publication:https://doi.org/10.1038/s41467-021-22491-8
PubMed:View item in PubMed

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