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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Cardiff Univ, MRC Ctr Neuropsychiat Genet & Gen, Inst Psychol Med & Clin Neurosci, Cardiff, S Glam, Wales..
Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands..
Univ Penn, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Dept Biostat & Epidemiol, Philadelphia, PA USA.;Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA..
Risk Factors & Mol Determinants Aging Related Dis, RID AGE, U1167, INSERM, Lille, France.;Inst Pasteur, Lille, France.;Univ Lille, Excellence Lab LabEx DISTALZ, U1167, Lille, France..
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2017 (English)In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 49, no 9, p. 1373-+Article in journal, Letter (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2017. Vol. 49, no 9, p. 1373-+
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Genetics
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URN: urn:nbn:se:uu:diva-334927DOI: 10.1038/ng.3916ISI: 000408672000016PubMedID: 28714976OAI: oai:DiVA.org:uu-334927DiVA, id: diva2:1161771
Available from: 2017-12-01 Created: 2017-12-01 Last updated: 2017-12-01Bibliographically approved

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Giedraitis, VilmantasLannfelt, LarsKilander, LenaBrundin, RoseMarieIngelsson, Martin

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