TYROBP genetic variants in early-onset Alzheimer's disease

• Published in: Neurobiology of aging Vol. 48; pp. 222.e9 - 222.e15
• Main Authors: Pottier, Cyril, Ravenscroft, Thomas A, Brown, Patricia H, Finch, NiCole A, Baker, Matt, Parsons, Meeia, Asmann, Yan W, Ren, Yingxue, Christopher, Elizabeth, Levitch, Denise, van Blitterswijk, Marka, Cruchaga, Carlos, Campion, Dominique, Nicolas, Gaël, Richard, Anne-Claire, Guerreiro, Rita, Bras, Jose T, Zuchner, Stephan, Gonzalez, Michael A, Bu, Guojun, Younkin, Steven, Knopman, David S, Josephs, Keith A, Parisi, Joseph E, Petersen, Ronald C, Ertekin-Taner, Nilüfer, Graff-Radford, Neill R, Boeve, Bradley F, Dickson, Dennis W, Rademakers, Rosa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adult; Aged; Aged, 80 and over; Alzheimer Disease - genetics; Alzheimer's disease; Burden test; Cohort Studies; Down-Regulation - genetics; Exome - genetics; Exome sequencing; Female; Gene Expression - genetics; Genetic Association Studies; Genetic Variation - genetics; HeLa Cells; Humans; Internal Medicine; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Membrane Proteins - genetics; Middle Aged; Mutation - genetics; Neurology; Receptors, Immunologic - genetics; Receptors, Immunologic - metabolism; Sequence Analysis; TREM2; TYROBP; TREM2; TYROBP; Alzheimer's disease; Burden test; Exome sequencing
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2016.07.028

Abstract We aimed to identify new candidate genes potentially involved in early-onset Alzheimer's disease (EOAD). Exome sequencing was conducted on 45 EOAD patients with either a family history of Alzheimer's disease (AD, <65 years) or an extremely early age at the onset (≤55 years) followed by multiple variant filtering according to different modes of inheritance. We identified 29 candidate genes potentially involved in EOAD, of which the gene TYROBP , previously implicated in AD, was selected for genetic and functional follow-up. Using 3 patient cohorts, we observed rare coding TYROBP variants in 9 out of 1110 EOAD patients, whereas no such variants were detected in 1826 controls ( p  = 0.0001), suggesting that at least some rare TYROBP variants might contribute to EOAD risk. Overexpression of the p.D50_L51ins14 TYROBP mutant led to a profound reduction of TREM2 expression, a well-established risk factor for AD. This is the first study supporting a role for genetic variation in TYROBP in EOAD, with in vitro support for a functional effect of the p.D50_L51ins14 TYROBP mutation on TREM2 expression.