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.
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Cyril
authors.initials: C
authors.lastname: Pottier
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ravenscroft
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Brown
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: NiCole A
authors.initials: NA
authors.lastname: Finch
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Baker
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Meeia
authors.initials: M
authors.lastname: Parsons
authors.affiliation: Division of Biomedical Statistics and Informatics, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Yingxue
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Christopher
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Denise
authors.initials: D
authors.lastname: Levitch
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Marka
authors.initials: M
authors.lastname: van Blitterswijk
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Cruchaga
authors.affiliation: 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.
authors.forename: Dominique
authors.initials: D
authors.lastname: Campion
authors.affiliation: 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.
authors.forename: Gaël
authors.initials: G
authors.lastname: Nicolas
authors.affiliation: Inserm U1079, Rouen University, Normandy Center for Genomic Medicine and Personalized Medicine, Normandy University, Rouen, France; CNR-MAJ, Rouen University Hospital, Rouen, France.
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Richard
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Guerreiro
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK.
authors.forename: Jose T
authors.initials: JT
authors.lastname: Bras
authors.affiliation: 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.
authors.forename: Stephan
authors.initials: S
authors.lastname: Zuchner
authors.affiliation: The Genesis Project Inc, Miami, FL, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Gonzalez
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Younkin
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Knopman
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Josephs
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.affiliation: Department of Neurology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Neill R
authors.initials: NR
authors.lastname: Graff-Radford
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Bradley F
authors.initials: BF
authors.lastname: Boeve
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. Electronic address: Rademakers.rosa@mayo.edu.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D015331:Cohort Studies; D015536:Down-Regulation / Q000235:genetics; D059472:Exome / Q000235:genetics; D005260:Female; D015870:Gene Expression / Q000235:genetics; D056726:Genetic Association Studies; D014644:Genetic Variation / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D017421:Sequence Analysis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; C498715:TREM2 protein, human; C110546:TYROBP protein, human
keywords: Alzheimer's disease; Burden test; Exome sequencing; TREM2; TYROBP