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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
Tuesday,2018-01-16 18:31 America/Los_Angeles — ecterry
| Title | Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. |
| Publication Type | Journal Article |
| Year of Publication | 2017 |
| Authors | 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, Nöthen, MM, White, CC, Hamilton-Nelson, KL, Epelbaum, J, Maier, W, Choi, S-H, Beecham, GW, Dulary, C, Herms, S, Smith, AV, Funk, CC, Derbois, C, Forstner, AJ, Ahmad, S, Li, H, Bacq, D, Harold, D, Satizabal, CL, Valladares, O, Squassina, A, Thomas, R, Brody, JA, Qu, L, Sánchez-Juan, P, Morgan, T, Wolters, FJ, Zhao, Y, Garcia, FSanchez, Denning, N, Fornage, M, Malamon, J, Naranjo, MCandida De, Majounie, E, Mosley, TH, Dombroski, B, Wallon, D, Lupton, MK, Dupuis, J, Whitehead, P, Fratiglioni, L, Medway, C, Jian, X, Mukherjee, S, Keller, L, Brown, K, Lin, H, Cantwell, LB, Panza, F, McGuinness, B, Moreno-Grau, S, Burgess, JD, Solfrizzi, V, Proitsi, P, Adams, HH, Allen, M, Seripa, D, Pastor, P, Cupples, AL, Price, ND, Hannequin, D, Frank-García, 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, Henández, 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, Jr, WTLongstre, Fairchild, TJ, Bossù, P, Lopez, OL, Frosch, MP, Sacchinelli, E, Ghetti, B, Yang, Q, Huebinger, RM, Jessen, F, Li, S, M Kamboh, I, 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, Fairén, MDíez, 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, MDonata, Ciaramella, A, Pichler, S, Mayhaus, M, Gu, W, Lleo, A, Fortea, J, Blesa, R, Barber, IS, Brookes, K, Cupidi, C, Maletta, RGiovanni, 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, C, Carlson, CS, Carlsson, CM, Carney, RM, Carrasquillo, MM, Carroll, SL, Diaz, CCeballos, 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, L-W, 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, Olichney, JM, 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, JPaul, Weintraub, S, Welsh-Bohmer, KA, Wilhelmsen, KC, Williamson, J, Wingo, TS, Woltjer, RL, Wright, CB, Yu, C-E, Yu, L, Garzia, F, Golamaully, F, Septier, G, Engelborghs, S, Vandenberghe, R, De Deyn, PP, Fernadez, CMuñoz, Benito, YAladro, Thonberg, H, Forsell, C, Lilius, L, Kinhult-Ståhlbom, A, Kilander, L, Brundin, RM, Concari, L, Helisalmi, S, Koivisto, AMaria, Haapasalo, A, Dermecourt, V, Fiévet, N, Hanon, O, Dufouil, C, Brice, A, Ritchie, K, Dubois, B, Himali, JJ, C Keene, D, Tschanz, JA, 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, ACecilia, 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, C-K, 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, J-F, DeStefano, AL, Ortega-Cubero, S, Hakonarson, H, Campion, D, Boada, M, Kauwe, JKeoni, Farrer, LA, Van Broeckhoven, C, Ikram, AM, Jones, L, Haines, JL, Tzourio, C, Launer, LJ, Escott-Price, V, Mayeux, R, Deleuze, J-F, Amin, N, Holmans, PA, Pericak-Vance, MA, Amouyel, P, van Duijn, CM, Ramirez, A, San Wang, L-, Lambert, J-C, Seshadri, S, Williams, J, Schellenberg, GD |
| Corporate/Institutional Authors | ARUK Consortium, GERAD/PERADES, CHARGE, ADGC, EADI |
| Journal | Nat Genet |
| Volume | 49 |
| Issue | 9 |
| Pagination | 1373-1384 |
| Date Published | 2017 Sep |
| ISSN | 1546-1718 |
| Keywords | Adaptor Proteins, Signal Transducing, Alzheimer Disease, Amino Acid Sequence, Case-Control Studies, Exome, Gene Expression Profiling, Gene Frequency, Genetic Predisposition to Disease, Genotype, Humans, Immunity, Innate, Linkage Disequilibrium, Membrane Glycoproteins, Microglia, Odds Ratio, Phospholipase C gamma, Polymorphism, Single Nucleotide, Protein Interaction Maps, Receptors, Immunologic, Sequence Homology, Amino Acid |
| Abstract | <p>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 × 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 × 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 × 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 × 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 × 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.</p> |
| DOI | 10.1038/ng.3916 |
| Alternate Journal | Nat. Genet. |
| PubMed ID | 28714976 |
| PubMed Central ID | PMC5669039 |
| Grant List | P30 AG013854 / AG / NIA NIH HHS / United States P50 MH060451 / MH / NIMH NIH HHS / United States P30 AG010124 / AG / NIA NIH HHS / United States U01 HG006375 / HG / NHGRI NIH HHS / United States RC2 AG036528 / AG / NIA NIH HHS / United States P30 AG028377 / AG / NIA NIH HHS / United States RF1 AG015819 / AG / NIA NIH HHS / United States N01 AG012100 / AG / NIA NIH HHS / United States P50 AG008671 / AG / NIA NIH HHS / United States P50 AG005142 / AG / NIA NIH HHS / United States N01 HC085081 / HC / NHLBI NIH HHS / United States P50 AG005131 / AG / NIA NIH HHS / United States R01 AG015928 / AG / NIA NIH HHS / United States R01 AG044546 / AG / NIA NIH HHS / United States P50 AG005128 / 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 U01 HL080295 / HL / NHLBI NIH HHS / United States P50 AG016574 / AG / NIA NIH HHS / United States P50 AG005146 / AG / NIA NIH HHS / United States R01 AG019085 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States RF1 AG053303 / AG / NIA NIH HHS / United States R01 AG013616 / AG / NIA NIH HHS / United States R01 AG030146 / AG / NIA NIH HHS / United States HHSN268200800007C / HL / NHLBI NIH HHS / United States P50 AG008702 / AG / NIA NIH HHS / United States UL1 RR029893 / RR / NCRR NIH HHS / United States Z99 AG999999 / / Intramural NIH HHS / United States N01 HC025195 / HC / NHLBI NIH HHS / United States 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 R01 AG017917 / AG / NIA NIH HHS / United States UL1 TR000124 / TR / NCATS NIH HHS / United States N01HC55222 / HL / NHLBI NIH HHS / United States R01 AG049607 / AG / NIA NIH HHS / United States P50 AG005136 / AG / NIA NIH HHS / United States P30 AG012300 / AG / NIA NIH HHS / United States N01HC85086 / HL / NHLBI NIH HHS / United States R01 HL105756 / HL / NHLBI NIH HHS / United States RF1 AG051504 / AG / NIA NIH HHS / United States R01 AG012101 / AG / NIA NIH HHS / United States R01 AG023651 / AG / NIA NIH HHS / United States P50 AG016573 / AG / NIA NIH HHS / United States P30 AG028740 / AG / NIA NIH HHS / United States U24 AG041689 / AG / NIA NIH HHS / United States P01 AG019724 / AG / NIA NIH HHS / United States P50 AG016570 / AG / NIA NIH HHS / United States P50 AG005134 / AG / NIA NIH HHS / United States P30 AG008017 / AG / NIA NIH HHS / United States HHSN268201200036C / HL / NHLBI NIH HHS / United States P30 AG010161 / AG / NIA NIH HHS / United States R01 AG033193 / AG / NIA NIH HHS / United States P50 AG025688 / AG / NIA NIH HHS / United States R01 AG032990 / AG / NIA NIH HHS / United States R37 AG015473 / AG / NIA NIH HHS / United States U24 AG026395 / AG / NIA NIH HHS / United States R01 NS080820 / NS / NINDS NIH HHS / United States HHSN268201500001I / HL / NHLBI NIH HHS / United States R01 CA129769 / CA / NCI NIH HHS / United States P50 AG005133 / AG / NIA NIH HHS / United States U01 AG010483 / AG / NIA NIH HHS / United States HHSN271201200022C / 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 R01 AG021547 / AG / NIA NIH HHS / United States R01 AG041232 / AG / NIA NIH HHS / United States P50 AG005138 / AG / NIA NIH HHS / United States R01 AG048927 / AG / NIA NIH HHS / United States R01 AG019757 / AG / NIA NIH HHS / United States R01 AG020688 / AG / NIA NIH HHS / United States U01 AG046139 / AG / NIA NIH HHS / United States R01 AG020098 / AG / NIA NIH HHS / United States N01HC85082 / HL / NHLBI NIH HHS / United States R01 AG030653 / AG / NIA NIH HHS / United States N01HC85083 / HL / NHLBI NIH HHS / United States R01 AG027944 / AG / NIA NIH HHS / United States R01 AG017173 / AG / NIA NIH HHS / United States R01 AG025259 / AG / NIA NIH HHS / United States P01 AG003949 / AG / NIA NIH HHS / United States U24 NS072026 / NS / NINDS NIH HHS / United States U01 HG004610 / HG / NHGRI NIH HHS / United States P30 AG010129 / AG / NIA NIH HHS / United States P30 AG019610 / AG / NIA NIH HHS / United States P50 AG016582 / AG / NIA NIH HHS / United States R01 AG041718 / AG / NIA NIH HHS / United States P50 AG025711 / AG / NIA NIH HHS / United States N01 HC085079 / HC / NHLBI NIH HHS / United States R01 AG023629 / AG / NIA NIH HHS / United States P30 AG028383 / AG / NIA NIH HHS / United States P01 AG017216 / AG / NIA NIH HHS / United States N01HC85080 / HL / NHLBI NIH HHS / United States R01 AG026916 / 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 R01 AG015819 / AG / NIA NIH HHS / United States IK2 BX001820 / BX / BLRD VA / United States U01 AG049505 / AG / NIA NIH HHS / United States |
ePub date:
17/09