Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
- PMID: 28714976
- PMCID: PMC5669039
- DOI: 10.1038/ng.3916
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
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.
Conflict of interest statement
Robert R. Graham and Timothy W. Behrens are full-time employees of Genentech Inc. Deborah Blacker is a consultant for Biogen Inc. Ronald C. Petersen is a consultant for Roche Inc., Merck Inc., Genentech Inc., Biogen Inc., and Eli Lilly. Ashley R. Winslow is a former employee and stockholder of Pfizer, Inc., and a current employee of the Perelman School of Medicine at the University of Pennsylvania Orphan Disease Center in partnership with the Loulou. Alison M. Goate is a member of the scientific advisory board for Denali Therapeutics. Nilufer Ertekin-Taner is a consultant for Cytox. John Hardy holds a collaborative grant with Cytox cofunded by Department of Business (Biz). Frank Jessen acts as a consultant for Novartis, Eli Lilly, Nutricia, MSD, Roche and Piramal. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. Dr. Morris is currently participating in clinical trials of antidementia drugs from Eli Lilly and Company, Biogen, and Janssen. Dr. Morris serves as a consultant for Lilly USA. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by NIH grants # P50AG005681; P01AG003991; P01AG026276 and UF01AG032438.
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Methods only References
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    - Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004. - PubMed
 
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