Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10(-4)) in 35,962 independent samples using de nov...

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Autores: Sims, R; van der Lee, SJ; Naj, AC; Bellenguez, C; Badarinarayan, N; Jakobsdottir, J; Kunkle, BW; Boland, A; Raybould, R; Bis, JC; Martin, ER; Grenier-Boley, B; Heilmann-Heimbach, S; Chouraki, V; Kuzma, AB; Sleegers, K; Vronskaya, M; Ruiz, A; Graham, RR; Olaso, R; Hoffmann, P; Grove, ML; Vardarajan, BN; Hiltunen, M; Nothen, MM; White, CC; Hamilton-Nelson, KL; Epelbaum, J; Maier, W; Choi, SH; Beecham, GW; Dulary, C; Herms, S; Smith, AV; Funk, CC; Derbois, C; Forstner, AJ; Ahmad, S; Li, HD; Bacq, D; Harold, D; Satizabal, CL; Valladares, O; Squassina, A; Thomas, R; Brody, JA; Qu, LM; Sanchez-Juan, P; Morgan, T; Wolters, FJ; Zhao, Y; Garcia, FS; Denning, N; Fornage, M; Malamon, J; Naranjo, MCD; Majounie, E; Mosley, TH; Dombroski, B; Wallon, D; Lupton, MK; Dupuis, J; Whitehead, P; Fratiglioni, L; Medway, C; Jian, XQ; Mukherjee, S; Keller, L; Brown, K; Lin, HH; Cantwell, LB; Panza, F; McGuinness, B; Moreno-Grau, S; Burgess, JD; Solfrizzi, V; Proitsi, P; Adams, HH; Allen, M; Seripa, D; Pastor, P; Cupples, LA; Price, ND; Hannequin, D; Frank-Garcia, A; Levy, D; Chakrabarty, P; Caffarra, P; Giegling, I; Beiser, AS; Giedraitis, V; Hampel, H; Garcia, ME; Wang, X; Lannfelt, L; Mecocci, P; Eiriksdottir, G; Crane, PK; Pasquier, F; Boccardi, V; Henandez, I; Barber, RC; Scherer, M; Tarraga, L; Adams, PM; Leber, M; Chen, Y; Albert, MS; Riedel-Heller, S; Emilsson, V; Beekly, D; Braae, A; Schmidt, R; Blacker, D; Masullo, C; Schmidt, H; Doody, RS; Spalletta, G; Longstreth, WT; Fairchild, TJ; Bossu, P; Lopez, OL; Frosch, MP; Sacchinelli, E; Ghetti, B; Yang, Q; Huebinger, RM; Jessen, F; Li, S; Kamboh, MI; Morris, J; Sotolongo-Grau, O; Katz, MJ; Corcoran, C; Dunstan, M; Braddel, A; Thomas, C; Meggy, A; Marshall, R; Gerrish, A; Chapman, J; Aguilar, M; Taylor, S; Hill, M; Fairen, MD; Hodges, A; Vellas, B; Soininen, H; Kloszewska, I; Daniilidou, M; Uphill, J; Patel, Y; Hughes, JT; Lord, J; Turton, J; Hartmann, AM; Cecchetti, R; Fenoglio, C; Serpente, M; Arcaro, M; Caltagirone, C; Orfei, MD; Ciaramella, A; Pichler, S; Mayhaus, M; Gu, W; Lleo, A; Forte, J; Blesa, R; Barber, IS; Brookes, K; Cupidi, C; Maletta, RG; Carrell, D; Sorbi, S; Moebus, S; Urbano, M; Pilotto, A; Kornhuber, J; Bosco, P; Todd, S; Craig, D; Johnston, J; Gill, M; Lawlor, B; Lynch, A; Fox, NC; Hardy, J; Albin, RL; Apostolova, LG; Arnold, SE; Asthana, S; Atwood, CS; Baldwin, CT; Barnes, LL; Barral, S; Beach, TG; Becker, JT; Bigio, EH; Bird, TD; Boeve, BF; Bowen, JD; Boxer, A; Burke, JR; Burns, JM; Buxbaum, JD; Cairns, NJ; Cao, CH; Carlson, CS; Carlsson, CM; Carney, RM; Carrasquillo, MM; Carroll, SL; Diaz, CC; Chui, HC; Clark, DG; Cribbs, DH; Crocco, EA; DeCarli, C; Dick, M; Duara, R; Evans, DA; Faber, KM; Fallon, KB; Fardo, DW; Farlow, MR; Ferris, S; Foroud, TM; Galasko, DR; Gearing, M; Geschwind, DH; Gilbert, JR; Graff-Radford, NR; Green, RC; Growdon, JH; Hamilton, RL; Harrell, LE; Honig, LS; Huentelman, MJ; Hulette, CM; Hyman, BT; Jarvik, GP; Abner, E; Jin, LW; Jun, G; Karydas, A; Kaye, JA; Kim, R; Kowall, NW; Kramer, JH; LaFerla, FM; Lah, JJ; Leverenz, JB; Levey, AI; Li, G; Lieberman, AP; Lunetta, KL; Lyketsos, CG; Marson, DC; Martiniuk, F; Mash, DC; Masliah, E; McCormick, WC; McCurry, SM; McDavid, AN; Mckee, AC; Mesulam, M; Miller, BL; Miller, CA; Miller, JW; Morris, JC; Murrell, JR; Myers, AJ; O'Bryant, S; Pankratz, VS; Parisi, JE; Paulson, HL; Perry, W; Peskind, E; Pierce, A; Poon, WW; Potter, H; Quinn, JF; Raj, A; Raskind, M; Reisberg, B; Reitz, C; Ringman, JM; Roberson, ED; Rogaeva, E; Rosen, HJ; Rosenberg, RN; Sager, MA; Saykin, AJ; Schneider, JA; Schneider, LS; Seeley, WW; Smith, AG; Sonnen, JA; Spina, S; Stern, RA; Swerdlow, RH; Tanzi, RE; Thornton-Wells, TA; Trojanowski, JQ; Troncoso, JC; Van Deerlin, VM; Van Eldik, LJ; Vinters, HV; Vonsattel, JP; Weintraub, S; Welsh-Bohmer, KA; Wilhelmsen, KC; Williamson, J; Woltjer, RL; Wright, CB; Yu, CE; Yu, L; Garzia, F; Golamaully, F; Septier, G; Engelborghs, S; Vandenberghe, R; De Deyn, PP; Fernadez, CM; Benito, YA; Thonberg, H; Forsell, C; Lilius, L; Kinhult-Stahlbom, A; Kilander, L; Brundin, R; Concari, L; Helisalmi, S; Koivisto, AM; Haapasalo, A; Dermecourt, V; Fievet, N; Hanon, O; Dufouil, C; Brice, A; Ritchie, K; Dubois, B; Himali, JJ; Keene, CD; Tschanz, J; Fitzpatrick, AL; Kukull, WA; Norton, M; Aspelund, T; Larson, EB; Munger, R; Rotter, JI; Lipton, RB; Bullido, MJ; Hofman, A; Montine, TJ; Coto, E; Boerwinkle, E; Petersen, RC; Alvarez, V; Rivadeneira, F; Reiman, EM; Gallo, M; O'Donnell, CJ; Reisch, JS; Bruni, AC; Royall, DR; Dichgans, M; Sano, M; Galimberti, D; St George-Hyslop, P; Scarpini, E; Tsuang, DW; Mancuso, M; Bonuccelli, U; Winslow, AR; Daniele, A; Wu, CK; Peters, O; Nacmias, B; Riemenschneider, M; Heun, R; Brayne, C; Rubinsztein, DC; Bras, J; Guerreiro, R; Al-Chalabi, A; Shaw, CE; Collinge, J; Mann, D; Tsolaki, M; Clarimon, J; Sussams, R; Lovestone, S; O'Donovan, MC; Owen, MJ; Behrens, TW; Mead, S; Goate, AM; Uitterlinden, AG; Holmes, C; Cruchaga, C; Ingelsson, M; Bennett, DA; Powell, J; Golde, TE; Graff, C; De Jager, PL; Morgan, K; Ertekin-Taner, N; Combarros, O; Psaty, BM; Passmore, P; Younkin, SG; Berr, C; Gudnason, V; Rujescu, D; Dickson, DW; Dartigues, JF; DeStefano, AL; Ortega-Cubero, S; Hakonarson, H; Campion, D; Boada, M; Kauwe, JK; Farrer, LA; Van Broeckhoven, C; Ikram, MA; Jones, L; Haines, JL; Tzourio, C; Launer, LJ; Escott-Price, V; Mayeux-, R; Deleuze, JF; Amin, N; Holmans, PA; Pericak-Vance, MA; Amouyel, P; van Duijn, CM; Ramirez, A; Wang, LS; Lambert, JC; Seshadri, S; Williams, J; Schellenberg, GD
Tipo de documento: Artigo
Estado:Published version
Data de publicação:2017
País:España
Recursos:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositório:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p14146
Acesso em linha:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=14146
https://europepmc.org/articles/pmc5669039
Nível de acesso:Acesso aberto
Resumo:We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 x 10(-4)) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 x 10(-8)) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p. Pro522Arg, P = 5.38 x 10(-10), odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p. Ser209Phe, P = 4.56 x 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p. Arg62His, P = 1.55 x 10(-14), OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

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