TREM2 Variants in Alzheimer's Disease

Abstract

BACKGROUND Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. METHODS We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. RESULTS We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. CONCLUSIONS Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.)

Genomics implicates adaptive and innate immunity in Alzheimer's and Parkinson's diseases

“…Findings are strongest for the innate immune response, for instance association with the TREM2 gene, which in brain cells are primarily expressed on microglia 45, 46. Our findings further support the role of immune variation in AD susceptibility.…”

Whole genome sequencing of Caribbean Hispanic families with late‐onset Alzheimer's disease

“…We also included known early‐onset AD genes and genes implicated in earlier sequencing efforts in LOAD 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16. Candidate genes evaluated included: APP, PSEN1, PSEN2, GRN, MAPT, TREM2, PLD3, APOE, ABCA7, SORL1, CR1, BIN1, CD2AP, EPHA1, CLU, MS4A6A, PICALM, CD33, HLA‐DRB5, HLA‐DRB1, PTK2B, SLC24A4, RIN3, INPP5D, MEF2C, NME8, ZCWPW1, CELF1, FERMT2, CASS4, TREML2, and AKAP9 .…”

“…Common variants identified through GWAS may not have functional consequences, simply reflecting linkage disequilibrium with the unobserved causal variants. It is also possible that these causal variants are rare and have large effects, such as TREM2, 7, 8, 9, 10, 11, 12, 13 and are not covered by commercially available GWAS platforms. In fact, putatively damaging variants have already been identified (for example TREM2 , SORL1, and ABCA7 ) in some of these LOAD susceptibility loci, advancing our understanding of disease risk 14, 15, 16…”

Aging and Alzheimer’s disease: Comparison and associations from molecular to system level

“…Changes related to microglia, the resident macrophages of the CNS, have long been considered to be secondary events to neurodegeneration but are now emerging as central to AD risk (Guerreiro et al, 2013; Jonsson et al, 2013; Lambert et al, 2013; Salter & Stevens, 2017; Zhang et al, 2013). GWAS repeatedly identified SNPs on TREM2, CD33, CD1, etc., which are all expressed on microglia and myeloid cells, as AD risk factors.…”