@article{3465f3a72aae4d3191e05e570c5db9bf,
title = "TYROBP genetic variants in early-onset Alzheimer's disease",
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.",
keywords = "Alzheimer's disease, Burden test, Exome sequencing, TREM2, TYROBP",
author = "Cyril Pottier and Ravenscroft, {Thomas A.} and Brown, {Patricia H.} and Finch, {Ni Cole A.} and Matt Baker and Meeia Parsons and Asmann, {Yan W.} and Yingxue Ren and Elizabeth Christopher and Denise Levitch and {van Blitterswijk}, Marka and Carlos Cruchaga and Dominique Campion and Ga{\"e}l Nicolas and Richard, {Anne Claire} and Rita Guerreiro and Bras, {Jose T.} and Stephan Zuchner and Gonzalez, {Michael A.} and Guojun Bu and Steven Younkin and Knopman, {David S.} and Josephs, {Keith A.} and Parisi, {Joseph E.} and Petersen, {Ronald C.} and Nil{\"u}fer Ertekin-Taner and Graff-Radford, {Neill R.} and Boeve, {Bradley F.} and Dickson, {Dennis W.} and Rosa Rademakers",
note = "Funding Information: This work was funded by the US National Institutes of Health ( P50-AG016574 , R01-NS080882 , R01-AG032990 , R01-NS080820 , U01-AG046139 , R21-AG048101 , and RF1-AG051504 ), and the Florida State Ed and Ethel Moore Alzheimer's Disease Research Program. Jose T. Bras and Rita Guerreiro are supported by Research Fellowships from Alzheimer's Society. Dominique Campion, Ga{\"e}l Nicolas, and Anne-Claire Richard were supported by France G{\'e}nomique National infrastructure, funded as part of “Investissement d'avenir” program managed by Agence Nationale pour la Recherche (contrat ANR-10-INBS-09), by the JPND “Perades Program” and by the Labex GENMED ANR- 10-LABX-0013. ",
year = "2016",
month = dec,
day = "1",
doi = "10.1016/j.neurobiolaging.2016.07.028",
language = "English (US)",
volume = "48",
pages = "222.e9--222.e15",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",
}