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Neurobiol Aging. 2016 Dec;48:222.e9-222.e15. doi: 10.1016/j.neurobiolaging.2016.07.028. Epub 2016 Aug 8.

TYROBP genetic variants in early-onset Alzheimer's disease.

Author information

1
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
2
Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
3
Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
4
Inserm U1079, Rouen University, Normandy Center for Genomic Medicine and Personalized Medicine, Normandy University, Rouen, France; CNR-MAJ, Rouen University Hospital, Rouen, France; Department of Research, Rouvray Psychiatric Hospital, Rouen, France.
5
Inserm U1079, Rouen University, Normandy Center for Genomic Medicine and Personalized Medicine, Normandy University, Rouen, France; CNR-MAJ, Rouen University Hospital, Rouen, France; Department of Genetics, Rouen University Hospital, Rouen, France.
6
Inserm U1079, Rouen University, Normandy Center for Genomic Medicine and Personalized Medicine, Normandy University, Rouen, France; CNR-MAJ, Rouen University Hospital, Rouen, France.
7
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
8
Dr John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
9
The Genesis Project Inc, Miami, FL, USA.
10
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
11
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
12
Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
13
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Rademakers.rosa@mayo.edu.

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

[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

statement The authors declare have no conflicts of interest to disclose. The ethics committees of all participating institutions have approved this study.

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