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

• Published in: Nature genetics Vol. 49; no. 9; pp. 1373 - 1384
• Main Authors: Badarinarayan, Nandini, Bis, Joshua C, Heilmann-Heimbach, Stefanie, Sleegers, Kristel, Vronskaya, Maria, White, Charles C, Hamilton-Nelson, Kara L, Choi, Seung-Hoan, Forstner, Andreas J, Bacq, Delphine, Brody, Jennifer A, Wolters, Frank J, Fornage, Myriam, Majounie, Elisa, Wallon, David, Lupton, Michelle K, Jian, Xueqiu, Mukherjee, Shubhabrata, Solfrizzi, Vincenzo, Allen, Mariet, Cupples, L Adrienne, Giegling, Ina, Giedraitis, Vilmantas, Wang, Xue, Mecocci, Patrizia, Eiriksdottir, Gudny, Chen, Yuning, Frosch, Matthew P, Huebinger, Ryan M, Morris, John, Sotolongo-Grau, Oscar, Katz, Mindy J, Braddel, Amy, Chapman, Jade, Hill, Matt, Vellas, Bruno, Soininen, Hilkka, Hughes, Joseph T, Mayhaus, Manuel, Maletta, Raffaele Giovanni, Carrell, David, Pilotto, Alberto, Fox, Nick C, Arnold, Steven E, Becker, James T, Burke, James R, Carlsson, Cynthia M, Clark, David G, Cribbs, David H, Duara, Ranjan, Evans, Denis A, Fallon, Kenneth B, Farlow, Martin R, Foroud, Tatiana M, Galasko, Douglas R, Jin, Lee-Way, Lah, James J, Levey, Allan I, Lieberman, Andrew P, McKee, Ann C, Morris, John C, Paulson, Henry L, Peskind, Elaine, Quinn, Joseph F, Raskind, Murray, Spina, Salvatore, Swerdlow, Russell H, Van Eldik, Linda J, Vinters, Harry V, Vonsattel, Jean Paul, De Deyn, Peter P, Concari, Letizia, Brice, Alexis, Dubois, Bruno, Tschanz, JoAnn, Fitzpatrick, Annette L, Kukull, Walter A, Bullido, María J, Coto, Eliecer, Reiman, Eric M, Gallo, Maura, Scarpini, Elio, Tsuang, Debby W, Bonuccelli, Ubaldo, Rubinsztein, David C, Bras, Jose, Guerreiro, Rita, Lovestone, Simon, Owen, Michael J, Cruchaga, Carlos, Powell, John, De Jager, Philip L, Rujescu, Dan, Ortega-Cubero, Sara, Ikram, M Arfan, Mayeux, Richard, Deleuze, Jean-François, Amin, Najaf, Amouyel, Philippe, van Duijn, Cornelia M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2017; Nature Publishing Group
• Subjects: 45/43; 631/208/205/2138; 692/699/375/365/1283; Adaptor Proteins, Signal Transducing - genetics; Agriculture; Alzheimer Disease - genetics; Alzheimer's disease; Amino Acid Sequence; Animal Genetics and Genomics; Bioinformatics; Biomedicine; Cancer Research; Case-Control Studies; Consortia; Development and progression; Disease control; DNA methylation; DNA microarrays; Exome - genetics; Gene Expression Profiling; Gene Frequency; Gene Function; Genes; Genetic aspects; Genetic Predisposition to Disease - genetics; Genetic variation; Genomes; Genomics; Genotype; Genotypes; Genotyping; Human Genetics; Humans; Immune response; Immune system; Immunity; Immunity (Disease); Immunity, Innate - genetics; Innate immunity; letter; Life Sciences; Linkage Disequilibrium; Membrane Glycoproteins - genetics; Microglia; Microglia - metabolism; Neurodegenerative diseases; Neurons and Cognition; Odds Ratio; Phospholipase C gamma - genetics; Physiological aspects; Polymorphism, Single Nucleotide; Protein interaction; Protein Interaction Maps - genetics; Proteins; Receptors, Immunologic - genetics; Sequence Homology, Amino Acid; Studies; United States; United Kingdom; Netherlands
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3916

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2 , ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of 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 × 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, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10 −10 , OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10 −14 , OR = 1.67, MAF cases = 0.0143, MAF controls = 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.