TREM2 Variants in Alzheimer’s disease

All the authors and their affiliations are listed in the Appendix.
New England Journal of Medicine (Impact Factor: 55.87). 11/2012; 368(2). DOI: 10.1056/NEJMoa1211851
Source: PubMed


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.

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.

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.

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.).

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    • "Statistical power was calculated by using the " Genetic Power Calculator " (http:// [13] considering an allelic OR of 2.5 [the lowest 95% confidence OR bound obtained in the original association of TREM2 p.R47H variant with AD [14]], a minor allele frequency (MAF) of 0.002 (the MAF available in 1000genomes dataset), a ¼ 0.05 and a disease prevalence of 4% [15]. For the Spanish dataset, the power to detect association was 44% and considering all series grouped, the power was >90% (Supplementary Table 1). "
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