TY - JOUR
T1 - Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
AU - Masullo, Carlo
AU - Spalletta, Gianfranco
AU - Orfei, Maria Donata
AU - Daniele, Antonio
PY - 2017
Y1 - 2017
N2 - 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 Ã 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 Ã 10 '8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs74905: p.Pro522Arg, P = 5.38 Ã 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 Ã 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 Ã 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 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.
AB - 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 Ã 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 Ã 10 '8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs74905: p.Pro522Arg, P = 5.38 Ã 10 '10, odds ratio (OR) = 0.68, minor allele frequency (MAF) cases = 0.0059, MAF controls = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 Ã 10 '10, OR = 1.43, MAF cases = 0.011, MAF controls = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 Ã 10 '14, OR = 1.67, MAF cases = 0.0143, MAF controls = 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.
KW - Adaptor Proteins, Signal Transducing
KW - Alzheimer Disease
KW - Amino Acid Sequence
KW - Case-Control Studies
KW - Exome
KW - Gene Expression Profiling
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genetics
KW - Genotype
KW - Humans
KW - Immunity, Innate
KW - Linkage Disequilibrium
KW - Membrane Glycoproteins
KW - Microglia
KW - Odds Ratio
KW - Phospholipase C gamma
KW - Polymorphism, Single Nucleotide
KW - Protein Interaction Maps
KW - Receptors, Immunologic
KW - Sequence Homology, Amino Acid
KW - Adaptor Proteins, Signal Transducing
KW - Alzheimer Disease
KW - Amino Acid Sequence
KW - Case-Control Studies
KW - Exome
KW - Gene Expression Profiling
KW - Gene Frequency
KW - Genetic Predisposition to Disease
KW - Genetics
KW - Genotype
KW - Humans
KW - Immunity, Innate
KW - Linkage Disequilibrium
KW - Membrane Glycoproteins
KW - Microglia
KW - Odds Ratio
KW - Phospholipase C gamma
KW - Polymorphism, Single Nucleotide
KW - Protein Interaction Maps
KW - Receptors, Immunologic
KW - Sequence Homology, Amino Acid
UR - http://hdl.handle.net/10807/106662
UR - http://www.nature.com/ng/index.html
U2 - 10.1038/ng.3916
DO - 10.1038/ng.3916
M3 - Article
VL - 49
SP - 1373
EP - 1384
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
ER -