Sims, Rebecca, van der Lee, Sven J, Naj, Adam C, Badarinarayan, Nandini, Morgan, Taniesha, Denning, Nicola, Majounie, Elisa, O'Donovan, Michael, Owen, Michael, Jones, Lesley, Escott-Price, Valentina, Holmans, Peter and Williams, Julie 2017. Rare coding variants in PLCG2, ABI3 and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. Nature Genetics 49 , pp. 1373-1384. 10.1038/ng.3916 |
|
PDF
- Accepted Post-Print Version
Download (2MB) | Preview |
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 |
---|---|
Date Type: | Publication |
Status: | Published |
Schools: | Advanced Research Computing @ Cardiff (ARCCA) Medicine Neuroscience and Mental Health Research Institute (NMHRI) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) |
Subjects: | R Medicine > R Medicine (General) |
Publisher: | Nature |
ISSN: | 1061-4036 |
Date of First Compliant Deposit: | 1 March 2017 |
Date of Acceptance: | 16 June 2016 |
Last Modified: | 25 Nov 2020 23:13 |
URI: | http://orca.cf.ac.uk/id/eprint/98651 |
Citation Data
Cited 239 times in Scopus. View in Scopus. Powered By Scopus® Data
Actions (repository staff only)
![]() |
Edit Item |