TY - JOUR
T1 - TYROBP genetic variants in early-onset Alzheimer's disease
AU - Pottier, Cyril
AU - Ravenscroft, Thomas A.
AU - Brown, Patricia H.
AU - Finch, Ni Cole A.
AU - Baker, Matt
AU - Parsons, Meeia
AU - Asmann, Yan W.
AU - Ren, Yingxue
AU - Christopher, Elizabeth
AU - Levitch, Denise
AU - van Blitterswijk, Marka
AU - Cruchaga, Carlos
AU - Campion, Dominique
AU - Nicolas, Gaël
AU - Richard, Anne Claire
AU - Guerreiro, Rita
AU - Bras, Jose T.
AU - Zuchner, Stephan
AU - Gonzalez, Michael A.
AU - Bu, Guojun
AU - Younkin, Steven
AU - Knopman, David S.
AU - Josephs, Keith A.
AU - Parisi, Joseph E.
AU - Petersen, Ronald C.
AU - Ertekin-Taner, Nilüfer
AU - Graff-Radford, Neill R.
AU - Boeve, Bradley F.
AU - Dickson, Dennis W.
AU - Rademakers, Rosa
N1 - Publisher Copyright:
© 2016 Elsevier Inc.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - Burden test
KW - Exome sequencing
KW - TREM2
KW - TYROBP
UR - http://www.scopus.com/inward/record.url?scp=84994544504&partnerID=8YFLogxK
U2 - 10.1016/j.neurobiolaging.2016.07.028
DO - 10.1016/j.neurobiolaging.2016.07.028
M3 - Article
C2 - 27658901
AN - SCOPUS:84994544504
SN - 0197-4580
VL - 48
SP - 222.e9-222.e15
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -