Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk

• DOI: 10.1093/braincomms/fcz022
• Publication Date: 2019-10-10T22:24:56Z
• Authors: Dervis A Salih; Sevinc Bayram; Sebastian Guelfi; Regina H Reynolds; Maryam Shoai; Mina Ryten; Jonathan W Brenton; David Zhang; Mar Matarin; Juan A Botia; Runil Shah; Keeley J Brookes; Tamar Guetta-Baranes; Kevin Morgan; Eftychia Bellou; Damian M Cummings; Valentina Escott-...; John Hardy
• Keywords: TREM2; Amyloid (mycology); Genetic Association

Abstract Genome-wide association studies of late-onset Alzheimer’s disease risk have previously identified genes primarily expressed in microglia that form a transcriptional network. Using transgenic mouse models amyloid deposition, we showed many the orthologues these are co-expressed and associated with pathology. In this new study, generate an improved RNA-seq-derived network is amyloid-responsive statistically compare gene-level variation previous human genome-wide to predict at least four for (OAS1, LAPTM5, ITGAM/CD11b LILRB4). Of Oas1a likely respond directly level, similarly established gene Trem2, because increase Trem2 transcripts response deposition mice significantly higher than both average microglial transcript number. contrast, LILRB4 (Laptm5, Itgam/CD11b Lilra5) show increased presence plaques similar magnitude number, except Laptm5 Lilra5 quicker as plaque load becomes dense. This work suggests genetic variability major determinant risk, identification may help developing disease. These findings also provide further insights into mechanisms underlying potential drug discovery.