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

TitleCommon variants in Alzheimer's disease and risk stratification by polygenic risk scores.
Publication TypeJournal Article
Year of Publication2021
Authorsde Rojas, I, Moreno-Grau, S, Tesi, N, Grenier-Boley, B, Andrade, V, Jansen, IE, Pedersen, NL, Stringa, N, Zettergren, A, Hernández, I, Montrreal, L, Antúnez, C, Antonell, A, Tankard, RM, Bis, JC, 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, JLuís, Moreno, F, Vilas, RHuerto, Baquero, M, Diez-Fairen, M, Lage, C, García-Madrona, S, García-González, P, Alarcón-Martín, E, Valero, S, Sotolongo-Grau, O, Ullgren, A, Naj, AC, Lemstra, AW, Benaque, A, Pérez-Cordón, A, Benussi, A, Rábano, A, Padovani, A, Squassina, A, de Mendonça, A, Pastor, AArias, Kok, AAL, Meggy, A, Pastor, ABelén, Espinosa, A, Corma-Gómez, A, Montes, AMartín, Sanabria, Á, DeStefano, AL, Schneider, A, Haapasalo, A, Ståhlbom, AKinhult, Tybjærg-Hansen, A, Hartmann, AM, Spottke, A, Corbatón-Anchuelo, A, Rongve, A, Borroni, B, Arosio, B, Nacmias, B, Nordestgaard, BG, Kunkle, BW, Charbonnier, C, Abdelnour, C, Masullo, C, Rodríguez, CMartínez, Muñoz-Fernandez, C, Dufouil, C, Graff, C, Ferreira, CB, Chillotti, C, Reynolds, CA, Fenoglio, C, Van Broeckhoven, C, Clark, C, Pisanu, C, Satizabal, CL, 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, IK, Alvarez, I, Appollonio, I, Giegling, I, Skoog, I, Saltvedt, I, Rainero, I, Allende, IRosas, Hort, J, Diehl-Schmid, J, Van Dongen, J, Vidal, J-S, Lehtisalo, J, Wiltfang, J, Thomassen, JQvist, Kornhuber, J, Haines, JL, Vogelgsang, J, Pineda, JA, Fortea, J, Popp, J, Deckert, J, Buerger, K, Morgan, K, Fließbach, K, Sleegers, K, Molina-Porcel, L, Kilander, L, Weinhold, L, Farrer, LA, San Wang, L-, Kleineidam, L, Farotti, L, Parnetti, L, Tremolizzo, L, Hausner, L, Benussi, L, Froelich, L, M Ikram, A, M Deniz-Naranjo, C, Tsolaki, M, Rosende-Roca, M, Löwenmark, M, Hulsman, M, Spallazzi, M, Pericak-Vance, MA, Esiri, M, Sánchez-Arjona, MBernal, Dalmasso, MCarolina, Martínez-Larrad, MTeresa, Arcaro, M, Nöthen, MM, Fernández-Fuertes, M, Dichgans, M, Ingelsson, M, Herrmann, MJ, Scherer, M, Vyhnalek, M, Kosmidis, MH, Yannakoulia, M, Schmid, M, Ewers, M, Heneka, MT, Wagner, M, Scamosci, M, Kivipelto, M, Hiltunen, M, Zulaica, M, Alegret, M, Fornage, M, Roberto, N, van Schoor, NM, Seidu, NM, Banaj, N, Armstrong, NJ, Scarmeas, N, Scherbaum, N, Goldhardt, O, Hanon, O, Peters, O, Skrobot, OAnna, Quenez, O, Lerch, O, Bossù, P, Caffarra, P, Rossi, PDionigi, Sakka, P, Mecocci, P, Hoffmann, P, Holmans, PA, Fischer, P, Riederer, P, Yang, Q, Marshall, R, Kalaria, RN, Mayeux, R, Vandenberghe, R, Cecchetti, R, Ghidoni, R, Frikke-Schmidt, R, Sorbi, S, Hägg, S, Engelborghs, S, Helisalmi, S, Sando, SBotne, 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, YAL, Kehoe, PGavin, Garcia-Ribas, G, Sánchez-Juan, P, Pastor, P, Pérez-Tur, J, Piñol-Ripoll, G, de Munain, ALopez, García-Alberca, JMaría, Bullido, MJ, Alvarez, V, Lleo, A, Real, LM, Mir, P, Medina, M, Scheltens, P, Holstege, H, Marquié, M, Sáez, MEugenia, Carracedo, Á, Amouyel, P, Schellenberg, GD, Williams, J, Seshadri, S, van Duijn, CM, Mather, KA, Sánchez-Valle, R, Serrano-Ríos, M, Orellana, A, Tarraga, L, Blennow, K, Huisman, M, Andreassen, OA, Posthuma, D, Clarimon, J, Boada, M, van der Flier, WM, Ramirez, A, Lambert, J-C, van der Lee, SJ, Ruiz, A
Corporate AuthorsEADB contributors, GR@ACE study group, DEGESCO consortium, IGAP (ADGC, CHARGE, EADI, GERAD), PGC-ALZ consortia
JournalNat Commun
Volume12
Issue1
Pagination3417
Date Published2021 Jun 07
ISSN2041-1723
KeywordsAge 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.
DOI10.1038/s41467-021-22491-8
Alternate JournalNat Commun
PubMed ID34099642
PubMed Central IDPMC8184987
Grant ListMC_PC_17112 / MRC_ / Medical Research Council / United Kingdom
R01 NS017950 / NS / NINDS NIH HHS / United States
G0902227 / MRC_ / Medical Research Council / United Kingdom
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG067501 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
MR/M009076/1 / MRC_ / Medical Research Council / United Kingdom
MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom
G0601022 / MRC_ / Medical Research Council / United Kingdom
MR/T04604X/1 / MRC_ / Medical Research Council / United Kingdom
N01AG12100 / AG / NIA NIH HHS / United States
082604/2/07/Z / WT_ / Wellcome Trust / United Kingdom
G9901400 / MRC_ / Medical Research Council / United Kingdom
U01 AG049505 / AG / NIA NIH HHS / United States
MC_UU_00024/1 / MRC_ / Medical Research Council / United Kingdom
U01 AG016976 / AG / NIA NIH HHS / United States
G0801418 / MRC_ / Medical Research Council / United Kingdom
R01 HL105756 / HL / NHLBI NIH HHS / United States
MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom
503480 / MRC_ / Medical Research Council / United Kingdom
P30 AG066462 / AG / NIA NIH HHS / United States
G1100540 / MRC_ / Medical Research Council / United Kingdom
U01 AG058589 / AG / NIA NIH HHS / United States
G0600237 / MRC_ / Medical Research Council / United Kingdom
G0300429 / MRC_ / Medical Research Council / United Kingdom
G0900652 / MRC_ / Medical Research Council / United Kingdom
G0400074 / MRC_ / Medical Research Council / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom
G0502157 / MRC_ / Medical Research Council / United Kingdom

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