학술논문

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores
Document Type
Author
de Rojas, I.Moreno-Grau, S.Tesi, N.Grenier-Boley, B.Andrade, V.Jansen, I. E.Pedersen, N. L.Stringa, N.Zettergren, A.Hernández, I.Montrreal, L.Antúnez, C.Antonell, A.Tankard, R. M.Bis, J. C.Sims, R.Bellenguez, C.Quintela, I.González-Perez, A.Calero, M.Franco-Macías, E.Macías, J.Blesa, R.Cervera-Carles, L.Menéndez-González, M.Frank-García, A.Royo, J. L.Moreno, F.Huerto Vilas, R.Baquero, M.Diez-Fairen, M.Lage, C.García-Madrona, S.García-González, P.Alarcón-Martín, E.Valero, S.Sotolongo-Grau, O.Ullgren, A.Naj, A. C.Lemstra, A. W.Benaque, A.Pérez-Cordón, A.Benussi, A.Rábano, A.Padovani, A.Squassina, A.de Mendonça, A.Arias Pastor, A.Kok, A. A. L.Meggy, A.Pastor, A. B.Espinosa, A.Corma-Gómez, A.Martín Montes, A.Sanabria, Á.DeStefano, A. L.Schneider, A.Haapasalo, A.Kinhult Ståhlbom, A.Tybjærg-Hansen, A.Hartmann, A. M.Spottke, A.Corbatón-Anchuelo, A.Rongve, A.Borroni, B.Arosio, B.Nacmias, B.Nordestgaard, B. G.Kunkle, B. W.Charbonnier, C.Abdelnour, C.Masullo, C.Martínez Rodríguez, C.Muñoz-Fernandez, C.Dufouil, C.Graff, C.Ferreira, C. B.Chillotti, C.Reynolds, C. A.Fenoglio, C.Van Broeckhoven, C.Clark, C.Pisanu, C.Satizabal, C. L.Holmes, C.Buiza-Rueda, D.Aarsland, D.Rujescu, D.Alcolea, D.Galimberti, D.Wallon, D.Seripa, D.Grünblatt, E.Dardiotis, E.Düzel, E.Scarpini, E.Conti, E.Rubino, E.Gelpi, E.Rodriguez-Rodriguez, E.Duron, E.Boerwinkle, E.Ferri, E.Tagliavini, F.Küçükali, F.Pasquier, F.Sanchez-Garcia, F.Mangialasche, F.Jessen, F.Nicolas, G.Selbæk, G.Ortega, G.Chêne, G.Hadjigeorgiou, G.Rossi, G.Spalletta, G.Giaccone, G.Grande, G.Binetti, G.Papenberg, G.Hampel, H.Bailly, H.Zetterberg, H.Soininen, H.Karlsson, Ida K.Alvarez, I.Appollonio, I.Giegling, I.Skoog, I.Saltvedt, I.Rainero, I.Rosas Allende, I.Hort, J.Diehl-Schmid, J.Van Dongen, J.Vidal, J. -SLehtisalo, J.Wiltfang, J.Thomassen, J. Q.Kornhuber, J.Haines, J. L.Vogelgsang, J.Pineda, J. A.Fortea, J.Popp, J.Deckert, J.Buerger, K.Morgan, K.Fließbach, K.Sleegers, K.Molina-Porcel, L.Kilander, L.Weinhold, L.Farrer, L. A.Wang, L. -SKleineidam, L.Farotti, L.Parnetti, L.Tremolizzo, L.Hausner, L.Benussi, L.Froelich, L.Ikram, M. A.Deniz-Naranjo, M. C.Tsolaki, M.Rosende-Roca, M.Löwenmark, M.Hulsman, M.Spallazzi, M.Pericak-Vance, M. A.Esiri, M.Bernal Sánchez-Arjona, M.Dalmasso, M. C.Martínez-Larrad, M. T.Arcaro, M.Nöthen, M. M.Fernández-Fuertes, M.Dichgans, M.Ingelsson, M.Herrmann, M. J.Scherer, M.Vyhnalek, M.Kosmidis, M. H.Yannakoulia, M.Schmid, M.Ewers, M.Heneka, M. T.Wagner, M.Scamosci, M.Kivipelto, M.Hiltunen, M.Zulaica, M.Alegret, M.Fornage, M.Roberto, N.van Schoor, N. M.Seidu, N. M.Banaj, N.Armstrong, N. J.Scarmeas, N.Scherbaum, N.Goldhardt, O.Hanon, O.Peters, O.Skrobot, O. A.Quenez, O.Lerch, O.Bossù, P.Caffarra, P.Dionigi Rossi, P.Sakka, P.Hoffmann, P.Holmans, P. A.Fischer, P.Riederer, P.Yang, Q.Marshall, R.Kalaria, R. N.Mayeux, R.Vandenberghe, R.Cecchetti, R.Ghidoni, R.Frikke-Schmidt, R.Sorbi, S.Hägg, S.Engelborghs, S.Helisalmi, S.Botne Sando, S.Kern, S.Archetti, S.Boschi, S.Fostinelli, S.Gil, S.Mendoza, S.Mead, S.Ciccone, S.Djurovic, S.Heilmann-Heimbach, S.Riedel-Heller, S.Kuulasmaa, T.del Ser, T.Lebouvier, T.Polak, T.Ngandu, T.Grimmer, T.Bessi, V.Escott-Price, V.Giedraitis, V.Deramecourt, V.Maier, W.Jian, X.Pijnenburg, Y. A. L.Smith, A. D.Saenz, A.Bizzarro, A.Lauria, A.Vacca, A.Solomon, A.Anastasiou, A.Richardson, A.Boland, A.Koivisto, A.Daniele, A.Greco, A.Marianthi, A.McGuinness, B.Fin, B.Ferrari, C.Custodero, C.Ferrarese, C.Ingino, C.Mangone, C.Reyes Toso, C.Martínez, C.Cuesta, C.Muchnik, C.Joachim, C.Ortiz, C.Besse, C.Johansson, C.Zoia, C. P.Laske, C.Anastasiou, C.Palacio, D. L.Politis, D. G.Janowitz, D.Craig, D.Mann, D. M.Neary, D.Jürgen, D.Daian, D.Belezhanska, D.Kohler, E.Castaño, E. M.Koutsouraki, E.Chipi, E.De Roeck, E.Costantini, E.Vardy, E. R. L. C.Piras, F.Roveta, F.Prestia, F. A.Assogna, F.Salani, F.Sala, G.Lacidogna, G.Novack, G.Wilcock, G.Thonberg, H.Kölsch, H.Weber, H.Boecker, H.Etchepareborda, I.Piaceri, I.Tuomilehto, J.Lindström, J.Laczo, J.Johnston, J.Deleuze, J. -FHarris, J.Schott, J. M.Priller, J.Bacha, J. I.Snowden, J.Lisso, J.Mihova, K. Y.Traykov, L.Morelli, L.Brusco, L. I.Rainer, M.Takalo, M.Bjerke, M.Del Zompo, M.Serpente, M.Sanchez Abalos, M.Rios, M.Peltonen, M.Herrman, M. J.Kohler, M.Rojo, M.Jones, M.Orsini, M.Medel, N.Olivar, N.Fox, N. C.Salvadori, N.Hooper, N. M.Galeano, P.Solis, P.Bastiani, P.Mecocci, P.Passmore, P.Heun, R.Antikainen, R.Olaso, R.Perneczky, R.Germani, S.López-García, S.Love, S.Mehrabian, S.Bagnoli, S.Kochen, S.Andreoni, S.Teipel, S.Todd, S.Pickering-Brown, S.Natunen, T.Tegos, T.Laatikainen, T.Strandberg, T.Polvikoski, T. M.Matoska, V.Ciullo, V.Cores, V.Solfrizzi, V.Lisetti, V.Sevillano, Z.Aguilera, N.Alarcon, E.Boada, M.Buendia, M.Cañabate, P.Carracedo, A.Diego, S.Gailhajenet, A.Guitart, M.González-Pérez, A.Ibarria, M.Lafuente, A.Macias, J.Maroñas, O.Martín, E.Martínez, M. T.Marquié, M.Mauleón, A.Moreno, M.Orellana, A.Pancho, A.Pelejá, E.Pérez-Cordon, A.Preckler, S.Real, L. M.Ruiz, A.Sáez, M. E.Sanabria, A.Serrano-Rios, M.Tárraga, L.Vargas, L.Adarmes-Gómez, A. D.Alonso, M. D.Álvarez, I.Álvarez, V.Amer-Ferrer, G.Antequera, M.Bernal, M.Bullido, M. J.Burguera, J. A.Carrillo, F.Carrión-Claro, M.Casajeros, M. J.Clarimón, J.Cruz-Gamero, J. M.de Pancorbo, M. M.Escuela, R.Garrote-Espina, L.García-Alberca, J. M.Garcia Madrona, S.Garcia-Ribas, G.Gómez-Garre, P.Hevilla, S.Jesús, S.Labrador Espinosa, M. A.Legaz, A.Lleó, A.Lopez de Munain, A.Macias-García, D.Manzanares, S.Marín, M.Marín-Muñoz, J.Marín, T.Martínez, B.Martínez, V.Martínez-Lage Álvarez, P.Medina, M.Mendioroz Iriarte, M.Mir, P.Molinuevo, J. L.Pastor, P.Pérez Tur, J.Periñán-Tocino, T.Pineda-Sanchez, R.Piñol-Ripoll, G.Real de Asúa, D.Rodrigo, S.Rodríguez-Rodríguez, E.Sanchez del Valle Díaz, R.Sánchez-Juan, P.Sastre, I.Vicente, M. P.Vigo-Ortega, R.Vivancos, L.Macleod, C.McCracken, C.Brayne, C.Bresner, C.Grozeva, D.Bellou, E.Sommerville, E. W.Matthews, F.Leonenko, G.Menzies, G.Windle, G.Harwood, J.Phillips, J.Bennett, K.Luckuck, L.Clare, L.Woods, R.Saad, S.Burholt, V.Kehoe, P. G.Pérez-Tur, J.Scheltens, P.Holstege, H.Carracedo, Á.Amouyel, P.Schellenberg, G. D.Williams, J.Seshadri, S.van Duijn, C. M.Mather, K. A.Sánchez-Valle, R.Serrano-Ríos, M.Blennow, K.Huisman, M.Andreassen, O. A.Posthuma, D.van der Flier, W. M.Ramirez, A.Lambert, J. -Cvan der Lee, S. J.contributors, EADBgroup, The GR@ACE studyconsortium, DEGESCOIGAP (ADGC, CHARGE, EADI, GERAD)consortia, PGC-ALZ
Source
Nature Communications. 12(1)
Subject
detection method
genetic analysis
nervous system disorder
public health
risk assessment
risk factor
stratification
amyloid precursor protein
apolipoprotein E
APP protein
human
aged
Alzheimer disease
case control study
cohort analysis
female
follow up
genetic predisposition
genetics
genome-wide association study
heterozygote
information processing
male
metabolism
middle aged
multifactorial inheritance
onset age
pathology
procedures
single nucleotide polymorphism
very elderly
Age of Onset
Aged
80 and over
Amyloid beta-Protein Precursor
Apolipoproteins E
Case-Control Studies
Cohort Studies
Datasets as Topic
Follow-Up Studies
Genetic Predisposition to Disease
Humans
Polymorphism
Single Nucleotide
Risk Factors
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.