Abstract
Rare variation in TREM2 has been associated with greater risk for Alzheimer’s disease (AD). TREM2 encodes a cell surface receptor expressed on microglia and related cells, and the R47H variant associated with AD appears to affect the ability of TREM2 to bind extracellular ligands. In addition, other rare TREM2 mutations causing early-onset neurodegeneration are thought to impair cell surface expression. Using a sequence kernel association (SKAT) analysis in two independent AD cohorts, we found significant enrichment of rare TREM2 variants not previously characterized at the protein level. Heterologous expression of the identified variants showed that novel variants S31F and R47C displayed significantly reduced cell surface expression. In addition, we identified rare variant R136Q in a patient with language-predominant AD that also showed impaired surface expression. The results suggest rare TREM2 variants enriched in AD may be associated with altered TREM2 function and that AD risk may be conferred, in part, from altered TREM2 surface expression.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0367-7) contains supplementary material, which is available to authorized users.
Highlights
Alzheimer’s disease (AD) is a common neurodegenerative disorder that occurs in older adults
The variants included in the TREM2 Single nucleotide polymorphism (SNP) set and their amino acid coding changes are summarized in Replication analysis in clinically diagnosed and pathologically confirmed AD We started with the same 157 genes available in the discovery analysis
Variants Y38C and T66M have been shown to have impaired cell surface expression [14, 37], and we demonstrate that the novel variants S31F and R47C, which localize to the Ig-like domain, show reduced surface expression
Summary
Alzheimer’s disease (AD) is a common neurodegenerative disorder that occurs in older adults. Aggregation of amyloid-β and hyperphosphorylated tau, which result in the formation of plaques and neurofibrillary tangles, respectively, represent the pathological hallmarks of AD. In addition to factors contributing to accumulation of amyloid and tau, changes in immune. Common variants like APOE ε4 are the best characterized genetic risk factors associated with AD. Rare genetic variation, which occurs at
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