title: Insights into TREM2 biology by network analysis of human brain gene expression data.
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.
authors.affiliation: Istituto di Genetica delle Popolazioni-CNR, Sassari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Forabosco
authors.forename: Adaikalavan
authors.initials: A
authors.lastname: Ramasamy
authors.forename: Daniah
authors.initials: D
authors.lastname: Trabzuni
authors.forename: Robert
authors.initials: R
authors.lastname: Walker
authors.forename: Colin
authors.initials: C
authors.lastname: Smith
authors.forename: Jose
authors.initials: J
authors.lastname: Bras
authors.forename: Adam P
authors.initials: AP
authors.lastname: Levine
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Pocock
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weale
authors.forename: Mina
authors.initials: M
authors.lastname: Ryten
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D015870:Gene Expression / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D017628:Microglia; D016472:Motor Neuron Disease / Q000235:genetics; D009103:Multiple Sclerosis / Q000235:genetics; D010587:Phagocytosis; D040081:Protein Array Analysis; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism
chemical_list: D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human
keywords: Alzheimer's disease; Immune system; Microglia; Post-mortem human brain; TREM2; Weighted gene co-expression network analysis