@article{3025522,
    title = "Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores",
    author = "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, V. and Maier, W. and Jian, X. and Pijnenburg, Y.A.L. and Smith, A.D. and Saenz, A. and Bizzarro, A. and Lauria, A. and Vacca, A. and Solomon, A. and Anastasiou, A. and Richardson, A. and Boland, A. and Koivisto, A. and Daniele, A. and Greco, A. and Marianthi, A. and McGuinness, B. and Fin, B. and Ferrari, C. and Custodero, C. and Ferrarese, C. and Ingino, C. and Mangone, C. and Reyes Toso, C. and Martínez, C. and Cuesta, C. and Muchnik, C. and Joachim, C. and Ortiz, C. and Besse, C. and Johansson, C. and Zoia, C.P. and Laske, C. and Anastasiou, C. and Palacio, D.L. and Politis, D.G. and Janowitz, D. and Craig, D. and Mann, D.M. and Neary, D. and Jürgen, D. and Daian, D. and Belezhanska, D. and Kohler, E. and Castaño, E.M. and Koutsouraki, E. and Chipi, E. and De Roeck, E. and Costantini, E. and Vardy, E.R.L.C. and Piras, F. and Roveta, F. and Piras, F. and Prestia, F.A. and Assogna, F. and Salani, F. and Sala, G. and Lacidogna, G. and Novack, G. and Wilcock, G. and Thonberg, H. and Kölsch, H. and Weber, H. and Boecker, H. and Etchepareborda, I. and Piaceri, I. and Tuomilehto, J. and Lindström, J. and Laczo, J. and Johnston, J. and Deleuze, J.-F. and Harris, J. and Schott, J.M. and Priller, J. and Bacha, J.I. and Snowden, J. and Lisso, J. and Mihova, K.Y. and Traykov, L. and Morelli, L. and Brusco, L.I. and Rainer, M. and Takalo, M. and Bjerke, M. and Del Zompo, M. and Serpente, M. and Sanchez Abalos, M. and Rios, M. and Peltonen, M. and Herrman, M.J. and Kosmidis, M.H. and Kohler, M. and Rojo, M. and Jones, M. and Orsini, M. and Medel, N. and Olivar, N. and Fox, N.C. and Salvadori, N. and Hooper, N.M. and Galeano, P. and Solis, P. and Bastiani, P. and Mecocci, P. and Passmore, P. and Heun, R. and Antikainen, R. and Olaso, R. and Perneczky, R. and Germani, S. and López-García, S. and Love, S. and Mehrabian, S. and Bagnoli, S. and Kochen, S. and Andreoni, S. and Teipel, S. and Todd, S. and Pickering-Brown, S. and Natunen, T. and Tegos, T. and Laatikainen, T. and Strandberg, T. and Polvikoski, T.M. and Matoska, V. and Ciullo, V. and Cores, V. and Solfrizzi, V. and Lisetti, V. and Sevillano, Z. and Abdelnour, C. and Aguilera, N. and Alarcon, E. and Alegret, M. and Benaque, A. and Boada, M. and Buendia, M. and Cañabate, P. and Carracedo, A. and Corbatón-Anchuelo, A. and Diego, S. and Espinosa, A. and Gailhajenet, A. and Gil, S. and Guitart, M. and Hernández, I. and Ibarria, M. and Lafuente, A. and Macias, J. and Maroñas, O. and Martín, E. and Martínez, M.T. and Marquié, M. and Mauleón, A. and Montrreal, L. and Moreno-Grau, S. and Moreno, M. and Orellana, A. and Ortega, G. and Pancho, A. and Pelejá, E. and Pérez-Cordon, A. and Pineda, J.A. and Preckler, S. and Quintela, I. and Real, L.M. and Rosende-Roca, M. and Ruiz, A. and Sáez, M.E. and Sanabria, A. and Serrano-Rios, M. and Sotolongo-Grau, O. and Tárraga, L. and Valero, S. and Vargas, L. and Adarmes-Gómez, A.D. and Alarcón-Martín, E. and Alonso, M.D. and Álvarez, I. and Álvarez, V. and Amer-Ferrer, G. and Antequera, M. and Antúnez, C. and Baquero, M. and Bernal, M. and Blesa, R. and Boada, M. and Buiza-Rueda, D. and Bullido, M.J. and Burguera, J.A. and Calero, M. and Carrillo, F. and Carrión-Claro, M. and Casajeros, M.J. and Clarimón, J. and Cruz-Gamero, J.M. and de Pancorbo, M.M. and del Ser, T. and Diez-Fairen, M. and Escuela, R. and Garrote-Espina, L. and Fortea, J. and Franco-Macías, E. and Frank-García, A. and García-Alberca, J.M. and Garcia Madrona, S. and Garcia-Ribas, G. and Gómez-Garre, P. and Hernández, I. and Hevilla, S. and Jesús, S. and Labrador Espinosa, M.A. and Lage, C. and Legaz, A. and Lleó, A. and Lopez de Munain, A. and López-García, S. and Macias-García, D. and Manzanares, S. and Marín, M. and Marín-Muñoz, J. and Marín, T. and Marquié, M. and Martín Montes, A. and Martínez, B. and Martínez, C. and Martínez, V. and Martínez-Lage Álvarez, P. and Medina, M. and Mendioroz Iriarte, M. and Mir, P. and Molinuevo, J.L. and Pastor, P. and Pérez Tur, J. and Periñán-Tocino, T. and Pineda-Sanchez, R. and Piñol-Ripoll, G. and Rábano, A. and Real de Asúa, D. and Rodrigo, S. and Rodríguez-Rodríguez, E. and Royo, J.L. and Ruiz, A. and Sanchez del Valle Díaz, R. and Sánchez-Juan, P. and Sastre, I. and Valero, S. and Vicente, M.P. and Vigo-Ortega, R. and Vivancos, L. and Macleod, C. and McCracken, C. and Brayne, C. and Bresner, C. and Grozeva, D. and Bellou, E. and Sommerville, E.W. and Matthews, F. and Leonenko, G. and Menzies, G. and Windle, G. and Harwood, J. and Phillips, J. and Bennett, K. and Luckuck, L. and Clare, L. and Woods, R. and Saad, S. and Burholt, V. and Jansen, I.E. and Rongve, A. 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 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. and EADB contributors and The GR@ACE study group and DEGESCO consortium and IGAP (ADGC, CHARGE, EADI, GERAD) and PGC-ALZ consortia",
    journal = "Nature Communications",
    year = "2021",
    volume = "12",
    number = "1",
    publisher = "Institute of Geographic Sciences and Natural Resources Research",
    issn = "2041-1723",
    doi = "10.1038/s41467-021-22491-8",
    keywords = "amyloid precursor protein;  apolipoprotein E4;  interleukin 34;  amyloid precursor protein;  apolipoprotein E;  APP protein, human, detection method;  genetic analysis;  nervous system disorder;  public health;  risk assessment;  risk factor;  stratification, adult;  Alzheimer disease;  Article;  case control study;  CHRNE gene;  female;  gene;  genetic association;  genetic linkage;  genetic risk;  genetic risk score;  genetic variation;  genotype;  heterozygote;  homozygote;  human;  major clinical study;  male;  missense mutation;  NDUFAF7 gene;  onset age;  PLCG2 gene;  population structure;  PRKD3 gene;  SHARPIN gene;  single nucleotide polymorphism;  aged;  Alzheimer disease;  cohort analysis;  follow up;  genetic predisposition;  genetics;  genome-wide association study;  information processing;  metabolism;  middle aged;  multifactorial inheritance;  pathology;  procedures;  risk assessment;  risk factor;  very elderly, Age of Onset;  Aged;  Aged, 80 and over;  Alzheimer Disease;  Amyloid beta-Protein Precursor;  Apolipoproteins E;  Case-Control Studies;  Cohort Studies;  Datasets as Topic;  Female;  Follow-Up Studies;  Genetic Predisposition to Disease;  Genome-Wide Association Study;  Heterozygote;  Humans;  Male;  Middle Aged;  Multifactorial Inheritance;  Polymorphism, Single Nucleotide;  Risk Assessment;  Risk Factors",
    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. © 2021, The Author(s)."
}