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

Accepted version
Peer-reviewed

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Type

Article

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Authors

Sims, Rebecca 
van der Lee, Sven J  ORCID logo  https://orcid.org/0000-0003-1606-8643
Bellenguez, Céline 
Badarinarayan, Nandini  ORCID logo  https://orcid.org/0000-0002-6944-748X

Abstract

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.

Description

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

Journal Title

Nat Genet

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

49

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MR/N012453/1)
Wellcome Trust (203249/Z/16/Z)
Wellcome Trust (095317/Z/11/Z)
European Commission Horizon 2020 (H2020) Societal Challenges (667375)
Medical Research Council (MC_G1000734)
Wellcome Trust (200110/Z/15/Z)
Medical Research Council (MR/L023784/2)
Medical Research Council (MR/L023784/1)