Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease.
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 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 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 LA., 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., Longstreth WT., Fairchild TJ., Bossù 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., Fairén 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., 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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 JK., Farrer LA., Van Broeckhoven C., Ikram MA., 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., Wang L-S., Lambert J-C., Seshadri S., Williams J., Schellenberg GD.
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.