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

Abstract

Introduction We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped 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, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development.

Microglia express ABI3 in the brains of Alzheimer's disease and Nasu-Hakola disease

“…A recent study identified p.Ser209Phe in the ABI3 gene as a risk variant for LOAD, although the expression of ABI3 in the human brain tissues remains to be determined (11). NHD is regarded as microgliopathy due to the complete loss of function of the TREM2-DAP12 signaling pathway in microglia, while AD is characterized by the partial loss of function of this pathway.…”

Genetik der Alzheimer-Krankheit

“…Bis heute gilt das Vorliegen von ein oder zwei Kopien des APOE ε4-Allels als stärkster Risikofaktor; nicht nur für die LOAD, sondern auch für die EOAD [2, 54,63]. Das humane Apolipoprotein E (ApoE) existiert in den drei Isoformen ApoE2, ApoE3 und ApoE4, welche die Genprodukte von drei AllelenanzweiEinzelnukleotidpolymorphismen ("single-nucleotide polymorphism", SNP), rs429358 und rs7412, sind und sich hinsichtlich ihrer Aminosäuren an den Positionen 112 und 158 unterscheiden (ApoE2: C112/C158, ApoE3: C112/R158, ApoE4: R112/R158) [ [56]. In den nächsten Abschnitten erfolgt eine detaillierte Beschreibung ausgewählter Kandidatengene, die mit immunsystembezogenen Prozessen der AD in Verbindung gebracht werden können.…”

Innate immunity and inflammation in Alzheimer´s disease pathogenesis

“…Variants in TREM2 -despite being less frequent in the population -have a similar effect size on the risk of developing AD to the one associated with the ε4 variant of the APOE (Apolipoprotein E) gene, the main genetic AD risk factor 4,5 . A more recent study that included almost 40,000 AD cases also identified ABI3 (ABI family member 3) and PLCG2 (phospholipase C gamma 2), genes that are highly expressed in microglia and encode proteins that participate in the immune response 5 . Inflammation is a complex and dynamic process, and during the course of AD, it probably has protective and deleterious effects in different phases 2,3 .…”

“…Since the mid-2000s, genome-wide association studies (GWAS) and association studies that used whole genome or exome sequencing data, have helped identify genes that are associated with late-onset AD; and by clustering those genes based on the analyses of biological pathways, four major pathways have been identified as implicated in the AD pathophysiology, one of which is immune response (and the others being control of endocytosis, cholesterol metabolism and ubiquitination of proteins) 4 . Genes such as CR1 (complement C3b/C4b receptor 1), CD33 (CD33 molecule), and TREM2 (triggering receptor expressed on myeloid cells 2) are expressed in microglia and encode proteins that participate in the microglial response to Aβ deposition 1,4,5 . Variants in TREM2 -despite being less frequent in the population -have a similar effect size on the risk of developing AD to the one associated with the ε4 variant of the APOE (Apolipoprotein E) gene, the main genetic AD risk factor 4,5 .…”

“…Genes such as CR1 (complement C3b/C4b receptor 1), CD33 (CD33 molecule), and TREM2 (triggering receptor expressed on myeloid cells 2) are expressed in microglia and encode proteins that participate in the microglial response to Aβ deposition 1,4,5 . Variants in TREM2 -despite being less frequent in the population -have a similar effect size on the risk of developing AD to the one associated with the ε4 variant of the APOE (Apolipoprotein E) gene, the main genetic AD risk factor 4,5 . A more recent study that included almost 40,000 AD cases also identified ABI3 (ABI family member 3) and PLCG2 (phospholipase C gamma 2), genes that are highly expressed in microglia and encode proteins that participate in the immune response 5 .…”