New insights into the genetic etiology of Alzheimer's disease and related dementias.

TitleNew insights into the genetic etiology of Alzheimer's disease and related dementias.
Publication TypeJournal Article
Year of Publication2022
AuthorsBellenguez, C, Küçükali, F, Jansen, IE, Kleineidam, L, Moreno-Grau, S, Amin, N, Naj, AC, Campos-Martin, R, Grenier-Boley, B, Andrade, V, Holmans, PA, Boland, A, Damotte, V, van der Lee, SJ, Costa, MR, Kuulasmaa, T, Yang, Q, de Rojas, I, Bis, JC, Yaqub, A, Prokic, I, Chapuis, J, Ahmad, S, Giedraitis, V, Aarsland, D, García-González, P, Abdelnour, C, Alarcón-Martín, E, Alcolea, D, Alegret, M, Alvarez, I, Alvarez, V, Armstrong, NJ, Tsolaki, A, Antúnez, C, Appollonio, I, Arcaro, M, Archetti, S, Pastor, AArias, Arosio, B, Athanasiu, L, Bailly, H, Banaj, N, Baquero, M, Barral, S, Beiser, A, Pastor, ABelén, Below, JE, Benchek, P, Benussi, L, Berr, C, Besse, C, Bessi, V, Binetti, G, Bizarro, A, Blesa, R, Boada, M, Boerwinkle, E, Borroni, B, Boschi, S, Bossù, P, Bråthen, G, Bressler, J, Bresner, C, Brodaty, H, Brookes, KJ, Brusco, LIgnacio, Buiza-Rueda, D, Bûrger, K, Burholt, V, Bush, WS, Calero, M, Cantwell, LB, Chêne, G, Chung, J, Cuccaro, ML, Carracedo, Á, Cecchetti, R, Cervera-Carles, L, Charbonnier, C, Chen, H-H, Chillotti, C, Ciccone, S, Claassen, JAHR, Clark, C, Conti, E, Corma-Gómez, A, Costantini, E, Custodero, C, Daian, D, Dalmasso, MCarolina, Daniele, A, Dardiotis, E, Dartigues, J-F, de Deyn, PPaul, Lopes, Kde Paiva, de Witte, LD, Debette, S, Deckert, J, Del Ser, T, Denning, N, DeStefano, A, Dichgans, M, Diehl-Schmid, J, Diez-Fairen, M, Rossi, PDionigi, Djurovic, S, Duron, E, Düzel, E, Dufouil, C, Eiriksdottir, G, Engelborghs, S, Escott-Price, V, Espinosa, A, Ewers, M, Faber, KM, Fabrizio, T, Nielsen, SFallgaard, Fardo, DW, Farotti, L, Fenoglio, C, Fernández-Fuertes, M, Ferrari, R, Ferreira, CB, Ferri, E, Fin, B, Fischer, P, Fladby, T, Fließbach, K, Fongang, B, Fornage, M, Fortea, J, Foroud, TM, Fostinelli, S, Fox, NC, Franco-Macías, E, Bullido, MJ, Frank-García, A, Froelich, L, Fulton-Howard, B, Galimberti, D, García-Alberca, JMaría, García-González, P, García-Madrona, S, Garcia-Ribas, G, Ghidoni, R, Giegling, I, Giorgio, G, Goate, AM, Goldhardt, O, Gomez-Fonseca, D, González-Perez, A, Graff, C, Grande, G, Green, E, Grimmer, T, Grünblatt, E, Grunin, M, Gudnason, V, Guetta-Baranes, T, Haapasalo, A, Hadjigeorgiou, G, Haines, JL, Hamilton-Nelson, KL, Hampel, H, Hanon, O, Hardy, J, Hartmann, AM, Hausner, L, Harwood, J, Heilmann-Heimbach, S, Helisalmi, S, Heneka, MT, Hernández, I, Herrmann, MJ, Hoffmann, P, Holmes, C, Holstege, H, Vilas, RHuerto, Hulsman, M, Humphrey, J, Biessels, GJan, Jian, X, Johansson, C, Jun, GR, Kastumata, Y, Kauwe, J, Kehoe, PG, Kilander, L, Ståhlbom, AKinhult, Kivipelto, M, Koivisto, A, Kornhuber, J, Kosmidis, MH, Kukull, WA, Kuksa, PP, Kunkle, BW, Kuzma, AB, Lage, C, Laukka, EJ, Launer, L, Lauria, A, Lee, C-Y, Lehtisalo, J, Lerch, O, Lleo, A, Longstreth, W, Lopez, O, de Munain, ALopez, Love, S, Löwemark, M, Luckcuck, L, Lunetta, KL, Ma, Y, Macías, J, MacLeod, CA, Maier, W, Mangialasche, F, Spallazzi, M, Marquié, M, Marshall, R, Martin, ER, Montes, AMartín, Rodríguez, CMartínez, Masullo, C, Mayeux, R, Mead, S, Mecocci, P, Medina, M, Meggy, A, Mehrabian, S, Mendoza, S, Menéndez-González, M, Mir, P, Moebus, S, Mol, M, Molina-Porcel, L, Montrreal, L, Morelli, L, Moreno, F, Morgan, K, Mosley, T, Nöthen, MM, Muchnik, C, Mukherjee, S, Nacmias, B, Ngandu, T, Nicolas, G, Nordestgaard, BG, Olaso, R, Orellana, A, Orsini, M, Ortega, G, Padovani, A, Paolo, C, Papenberg, G, Parnetti, L, Pasquier, F, Pastor, P, Peloso, G, Pérez-Cordón, A, Pérez-Tur, J, Pericard, P, Peters, O, Pijnenburg, YAL, Pineda, JA, Piñol-Ripoll, G, Pisanu, C, Polak, T, Popp, J, Posthuma, D, Priller, J, Puerta, R, Quenez, O, Quintela, I, Thomassen, JQvist, Rábano, A, Rainero, I, Rajabli, F, Ramakers, I, Real, LM, Reinders, MJT, Reitz, C, Reyes-Dumeyer, D, Ridge, P, Riedel-Heller, S, Riederer, P, Roberto, N, Rodriguez-Rodriguez, E, Rongve, A, Allende, IRosas, Rosende-Roca, M, Royo, JLuís, Rubino, E, Rujescu, D, Sáez, MEugenia, Sakka, P, Saltvedt, I, Sanabria, Á, Sánchez-Arjona, MBernal, Sanchez-Garcia, F, Juan, PSánchez, Sánchez-Valle, R, Sando, SB, Sarnowski, C, Satizabal, CL, Scamosci, M, Scarmeas, N, Scarpini, E, Scheltens, P, Scherbaum, N, Scherer, M, Schmid, M, Schneider, A, Schott, JM, Selbæk, G, Seripa, D, Serrano, M, Sha, J, Shadrin, AA, Skrobot, O, Slifer, S, Snijders, GJL, Soininen, H, Solfrizzi, V, Solomon, A, Song, Y, Sorbi, S, Sotolongo-Grau, O, Spalletta, G, Spottke, A, Squassina, A, Stordal, E, Tartan, JPablo, Tarraga, L, Tesi, N, Thalamuthu, A, Thomas, T, Tosto, G, Traykov, L, Tremolizzo, L, Tybjærg-Hansen, A, Uitterlinden, A, Ullgren, A, Ulstein, I, Valero, S, Valladares, O, Van Broeckhoven, C, Vance, J, Vardarajan, BN, van der Lugt, A, Van Dongen, J, van Rooij, J, van Swieten, J, Vandenberghe, R, Verhey, F, Vidal, J-S, Vogelgsang, J, Vyhnalek, M, Wagner, M, Wallon, D, San Wang, L-, Wang, R, Weinhold, L, Wiltfang, J, Windle, G, Woods, B, Yannakoulia, M, Zare, H, Zhao, Y, Zhang, X, Zhu, C, Zulaica, M, Farrer, LA, Psaty, BM, Ghanbari, M, Raj, T, Sachdev, P, Mather, K, Jessen, F, M Ikram, A, de Mendonça, A, Hort, J, Tsolaki, M, Pericak-Vance, MA, Amouyel, P, Williams, J, Frikke-Schmidt, R, Clarimon, J, Deleuze, J-F, Rossi, G, Seshadri, S, Andreassen, OA, Ingelsson, M, Hiltunen, M, Sleegers, K, Schellenberg, GD, van Duijn, CM, Sims, R, van der Flier, WM, Ruiz, A, Ramirez, A, Lambert, J-C
Corporate AuthorsEADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE
JournalNat Genet
Volume54
Issue4
Pagination412-436
Date Published2022 Apr
ISSN1546-1718
KeywordsAlzheimer Disease, Cognitive Dysfunction, Genome-Wide Association Study, Humans, tau Proteins
Abstract

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
DOI10.1038/s41588-022-01024-z
Alternate JournalNat Genet
PubMed ID35379992
PubMed Central IDPMC9005347
Grant ListN01HC55222 / HL / NHLBI NIH HHS / United States
P30 AG013854 / AG / NIA NIH HHS / United States
P30 AG053760 / AG / NIA NIH HHS / United States
P30 AG066444 / AG / NIA NIH HHS / United States
K08 AG065463 / AG / NIA NIH HHS / United States
MR/R024804/1 / MRC_ / Medical Research Council / United Kingdom
UL1 TR001445 / TR / NCATS NIH HHS / United States
N01HC85080 / HL / NHLBI NIH HHS / United States
G0801418/1 / MRC_ / Medical Research Council / United Kingdom
MC_PC_17112 / MRC_ / Medical Research Council / United Kingdom
R01 AG022374 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
R01 HL103612 / HL / NHLBI NIH HHS / United States
R56 AG057191 / AG / NIA NIH HHS / United States
U01 AG046152 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
U01 AG058654 / AG / NIA NIH HHS / United States
R01 NS017950 / NS / NINDS NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
MR/L023784/1 / MRC_ / Medical Research Council / United Kingdom
R01 AG054005 / AG / NIA NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
G0902227 / MRC_ / Medical Research Council / United Kingdom
R01 AG054076 / AG / NIA NIH HHS / United States
R01 HL120393 / HL / NHLBI NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
RF1 AG059421 / AG / NIA NIH HHS / United States
R01 AG035137 / AG / NIA NIH HHS / United States
R01 AG062622 / AG / NIA NIH HHS / United States
R01 AG009029 / AG / NIA NIH HHS / United States
HHSN268201800001C / HL / NHLBI NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
R01 AG009956 / AG / NIA NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P30 AG066511 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
U24 AG072122 / AG / NIA NIH HHS / United States
T32 EY007157 / EY / NEI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
P01 AG017586 / AG / NIA NIH HHS / United States
P30 AG066512 / AG / NIA NIH HHS / United States
U01 AG061356 / AG / NIA NIH HHS / United States
K99 AG066849 / AG / NIA NIH HHS / United States
RC2 AG036650 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
U01 HG008657 / HG / NHGRI NIH HHS / United States
U01 HL130114 / HL / NHLBI NIH HHS / United States
R56 AG055824 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
R01 AG013616 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
P20 MD000546 / MD / NIMHD NIH HHS / United States
75N92021D00006 / HL / NHLBI NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
MR/L010305/1 / MRC_ / Medical Research Council / United Kingdom
R01 AG017173 / AG / NIA NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
/ DH_ / Department of Health / United Kingdom
U01 AG016976 / AG / NIA NIH HHS / United States
P50 NS039764 / NS / NINDS NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
RC2 AG036502 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30 AG072980 / AG / NIA NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
MR/L501517/1 / MRC_ / Medical Research Council / United Kingdom
N01HC85082 / HL / NHLBI NIH HHS / United States
MR/K013041/1 / MRC_ / Medical Research Council / United Kingdom
R01 AG028786 / AG / NIA NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
R01 AG049607 / AG / NIA NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
G0601022 / MRC_ / Medical Research Council / United Kingdom
P50 AG005136 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
MR/T04604X/1 / MRC_ / Medical Research Council / United Kingdom
R21 AG063130 / AG / NIA NIH HHS / United States
RF1 AG059319 / AG / NIA NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
P30 AG062422 / AG / NIA NIH HHS / United States
R01 AG037985 / AG / NIA NIH HHS / United States
U19 AG024904 / AG / NIA NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
F99 AG073565 / AG / NIA NIH HHS / United States
R01 AG012101 / AG / NIA NIH HHS / United States
R01 AG023651 / AG / NIA NIH HHS / United States
U01 DK066134 / DK / NIDDK NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P30 AG066462 / AG / NIA NIH HHS / United States
N01HC85083 / HL / NHLBI NIH HHS / United States
P30 AG008017 / AG / NIA NIH HHS / United States
R01 AG042437 / AG / NIA NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
MR/L501529/1 / MRC_ / Medical Research Council / United Kingdom
N01HC85079 / HL / NHLBI NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
P30 AG066530 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
P30 ES030285 / ES / NIEHS NIH HHS / United States
R01 AG036042 / AG / NIA NIH HHS / United States
U01 AG058589 / AG / NIA NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
R37 AG015473 / AG / NIA NIH HHS / United States
P01 AG066597 / AG / NIA NIH HHS / United States
G0300429 / MRC_ / Medical Research Council / United Kingdom
R01 NS080820 / NS / NINDS NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
P30 AG066509 / AG / NIA NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
RC2 AG036547 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
P50 AG005144 / AG / NIA NIH HHS / United States
P01 AG010491 / AG / NIA NIH HHS / United States
P30 AG066546 / AG / NIA NIH HHS / United States
R01 AG033040 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
UKDRI-2002 / MRC_ / Medical Research Council / United Kingdom
R01 AG048927 / AG / NIA NIH HHS / United States
RF1 AG057473 / AG / NIA NIH HHS / United States
R01 AG037212 / AG / NIA NIH HHS / United States
ALCHALABI-DOBSON/APR14/829-791 / MNDA_ / Motor Neurone Disease Association / United Kingdom
U01 AG052409 / AG / NIA NIH HHS / United States
U01 AG068880 / AG / NIA NIH HHS / United States
R01 AG021547 / AG / NIA NIH HHS / United States
R01 AG041232 / AG / NIA NIH HHS / United States
R01 AG019757 / AG / NIA NIH HHS / United States
R01 AG020688 / AG / NIA NIH HHS / United States
R01 AG022018 / AG / NIA NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States
P30 AG072977 / AG / NIA NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
U19 AG062418 / AG / NIA NIH HHS / United States
R01 NS118146 / NS / NINDS NIH HHS / United States
G9901400 / MRC_ / Medical Research Council / United Kingdom
U24 NS072026 / NS / NINDS NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
UH2 NS100605 / NS / NINDS NIH HHS / United States
RF1 AG061872 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
P01 AG003949 / AG / NIA NIH HHS / United States
RF1 AG057519 / AG / NIA NIH HHS / United States
P30 AG062715 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
P30 AG072976 / AG / NIA NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
U01 AG046161 / AG / NIA NIH HHS / United States
R01 AG011101 / AG / NIA NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
R01 AG048015 / AG / NIA NIH HHS / United States
R01 AG041718 / AG / NIA NIH HHS / United States
P50 AG025711 / AG / NIA NIH HHS / United States
HHSN268200800007C / HL / NHLBI NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
RF1 AG061351 / AG / NIA NIH HHS / United States
MR/L023784/2 / MRC_ / Medical Research Council / United Kingdom
G0701075 / MRC_ / Medical Research Council / United Kingdom
P30 AG072972 / AG / NIA NIH HHS / United States
N01HC85081 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
P30 AG066514 / AG / NIA NIH HHS / United States
G0901254 / MRC_ / Medical Research Council / United Kingdom
P30 AG028383 / AG / NIA NIH HHS / United States
P01 AG017216 / AG / NIA NIH HHS / United States
P50 AG033514 / AG / NIA NIH HHS / United States
R01 NS059873 / NS / NINDS NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
U01 AG006786 / AG / NIA NIH HHS / United States
U19 AG068753 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
P30 AG072979 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States

Similar Publications

Zuo Z, Cheng X, Ferdous S, Shao J, Li J, Bao Y, et al.. Single cell dual-omic atlas of the human developing retina. Nat Commun. 2024;15(1):6792.
Banks E, Francis V, Lin S-J, Kharfallah F, Fonov V, Levesque M, et al.. Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy. Nat Commun. 2024;15(1):7239.
Chen F, Zhang Y, Shen L, Creighton CJ. The DNA methylome of pediatric brain tumors appears shaped by structural variation and predicts survival. Nat Commun. 2024;15(1):6775.