Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease

Sims, Rebecca and van der Lee, Sven J. and Naj, Adam C. and Bellenguez, Céline and Badarinarayan, Nandini and Jakobsdottir, Johanna and Kunkle, Brian W. and Boland, Anne and Raybould, Rachel and Bis, Josha C. and Martin, Eden R. and Grenier-Boley, Benjamin and Brown, Kristelle and Braae, Anne (2017) Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglialmediated innate immunity in Alzheimer’s disease. Nature Genetics . ISSN 1546-1718

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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.

Item Type: Article
Additional Information: 245 authors in total.
Schools/Departments: University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences > School of Molecular Medical Sciences > Human Genetics Research Group
University of Nottingham, UK > Faculty of Medicine and Health Sciences > School of Life Sciences
Identification Number: 10.1038/ng.3916
Depositing User: Morgan, Kevin
Date Deposited: 03 Aug 2017 08:40
Last Modified: 20 Aug 2017 04:09
URI: http://eprints.nottingham.ac.uk/id/eprint/40053

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