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  • Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
    van der Lee, Sven J; Jakobsdottir, Johanna; Boland, Anne; Grenier-Boley, Benjamin; Olaso, Robert; Beecham, Gary W; Derbois, Céline; Bacq, Delphine; Satizabal, Claudia L; Squassina, Alessio; Zhao, Yi; Denning, Nicola; Dombroski, Beth; Whitehead, Patrice; Lin, Honghuang; McGuinness, Bernadette; Allen, Mariet; Price, Nathan D; Caffarra, Paolo; Hampel, Harald; Boccardi, Virginia; Scherer, Martin; Braae, Anne; Masullo, Carlo; Schmidt, Helena; Doody, Rachelle S; Spalletta, Gianfranco; Fairchild, Thomas J; Lopez, Oscar L; Sacchinelli, Eleonora; Ghetti, Bernardino; Jessen, Frank; Sotolongo-Grau, Oscar; Katz, Mindy J; Meggy, Alun; Taylor, Sarah; Hodges, Angela; Vellas, Bruno; Kloszewska, Iwona; Hughes, Joseph T; Lord, Jenny; Gu, Wei; Blesa, Rafael; Brookes, Keeley; Carrell, David; Pilotto, Alberto; Todd, Stephen; Craig, David; Fox, Nick C; Arnold, Steven E; Atwood, Craig S; Barral, Sandra; Bowen, James D; Cao, Chuanhai; Cribbs, David H; DeCarli, Charles; Duara, Ranjan; Fardo, David W; Galasko, Douglas R; Gearing, Marla; Harrell, Lindy E; Huentelman, Matthew J; Jarvik, Gail P; Jun, Gyungah; Karydas, Anna; Lyketsos, Constantine G; Marson, Daniel C; Morris, John C; Myers, Amanda J; Pankratz, Vernon S; Parisi, Joseph E; Poon, Wayne W; Reitz, Christiane; Roberson, Erik D; Stern, Robert A; Trojanowski, John Q; Vinters, Harry V; Welsh-Bohmer, Kathleen A; Forsell, Charlotte; Kilander, Lena; Concari, Letizia; Dermecourt, Vincent; Keene, C Dirk; Kukull, Walter A; Larson, Eric B; Rotter, Jerome I; Scarpini, Elio; Riemenschneider, Matthias; O'Donovan, Michael C; Goate, Alison M; Uitterlinden, Andre G; Younkin, Steven G; Berr, Claudine; Dartigues, Jean-François; Boada, Merce; Haines, Jonathan L; Tzourio, Christophe; Amin, Najaf; Amouyel, Philippe; Ramirez, Alfredo

    Nature genetics, 09/2017, Letnik: 49, Številka: 9
    Journal Article

    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 ) 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 ) 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 , odds ratio (OR) = 0.68, minor allele frequency (MAF) = 0.0059, MAF = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 , OR = 1.43, MAF = 0.011, MAF = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 , OR = 1.67, MAF = 0.0143, MAF = 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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