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Abstract
Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes.
Highlights
Alzheimer’s disease (AD) is the most important cause of presenile dementia worldwide
We show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer’s disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes
We focus our analysis on the TREM2-containing modules and compare through preservation statistics the overlap between TREM2-containing modules in different brain regions and different data sets to better understand the function of this gene and its relationship to other known AD-related genes
Summary
Alzheimer’s disease (AD) is the most important cause of presenile dementia worldwide. In the last 3 years, there has been growing evidence for the importance of genetic risk factors in AD pathogenesis with the discovery of 10 new loci from genome-wide association studies (GWAS) (Hollingworth et al, 2011; Naj et al, 2011), and, most recently, the identification of heterozygous rare variants in TREM2 as a cause of increased susceptibility to late-onset AD (Guerreiro et al, 2012; Jonsson et al, 2012). Since TREM2 itself has no intracellular signaling motif, it is thought to be completely dependent on the adaptor protein TYROBP ( known as DAP12) for its downstream effects. Consistent with this view is the fact that homozygous loss-offunction mutations in either TREM2 or TYROBP result in NasueHakola disease
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