TYROBP genetic variants in early-onset Alzheimer's disease

Cyril Pottier; Thomas A. Ravenscroft; Patricia H. Brown; Ni Cole A. Finch; Matt Baker; Meeia Parsons; Yan W. Asmann; Yingxue Ren; Elizabeth Christopher; Denise Levitch; Marka van Blitterswijk; Carlos Cruchaga; Dominique Campion; Gaël Nicolas; Anne Claire Richard; Rita Guerreiro; Jose T. Bras; Stephan Zuchner; Michael A. Gonzalez; Guojun Bu; Steven Younkin; David S. Knopman; Keith A. Josephs; Joseph E. Parisi; Ronald C. Petersen; Nilüfer Ertekin-Taner; Neill R. Graff-Radford; Bradley F. Boeve; Dennis W. Dickson; Rosa Rademakers

doi:10.1016/j.neurobiolaging.2016.07.028

TYROBP genetic variants in early-onset Alzheimer's disease

Cyril Pottier, Thomas A. Ravenscroft, Patricia H. Brown, Ni Cole A. Finch, Matt Baker, Meeia Parsons, Yan W. Asmann, Yingxue Ren, Elizabeth Christopher, Denise Levitch, Marka van Blitterswijk, Carlos Cruchaga, Dominique Campion, Gaël Nicolas, Anne Claire Richard, Rita Guerreiro, Jose T. Bras, Stephan Zuchner, Michael A. Gonzalez, Guojun BuSteven Younkin, David S. Knopman, Keith A. Josephs, Joseph E. Parisi, Ronald C. Petersen, Nilüfer Ertekin-Taner, Neill R. Graff-Radford, Bradley F. Boeve, Dennis W. Dickson, Rosa Rademakers

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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.

Original language	English (US)
Pages (from-to)	222.e9-222.e15
Journal	Neurobiology of aging
Volume	48
DOIs	https://doi.org/10.1016/j.neurobiolaging.2016.07.028
State	Published - Dec 1 2016

Keywords

Alzheimer's disease
Burden test
Exome sequencing
TREM2
TYROBP

ASJC Scopus subject areas

Neuroscience(all)
Aging
Clinical Neurology
Developmental Biology
Geriatrics and Gerontology

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10.1016/j.neurobiolaging.2016.07.028

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Pottier, C., Ravenscroft, T. A., Brown, P. H., Finch, N. C. A., Baker, M., Parsons, M., Asmann, Y. W., Ren, Y., Christopher, E., Levitch, D., van Blitterswijk, M., Cruchaga, C., Campion, D., Nicolas, G., Richard, A. C., Guerreiro, R., Bras, J. T., Zuchner, S., Gonzalez, M. A., ... Rademakers, R. (2016). TYROBP genetic variants in early-onset Alzheimer's disease. Neurobiology of aging, 48, 222.e9-222.e15. https://doi.org/10.1016/j.neurobiolaging.2016.07.028

Pottier, C, Ravenscroft, TA, Brown, PH, Finch, NCA, Baker, M, Parsons, M, Asmann, YW , Ren, Y, Christopher, E, Levitch, D, van Blitterswijk, M, Cruchaga, C, Campion, D, Nicolas, G, Richard, AC, Guerreiro, R, Bras, JT, Zuchner, S, Gonzalez, MA, Bu, G , Younkin, S , Knopman, DS , Josephs, KA, Parisi, JE, Petersen, RC , Ertekin-Taner, N , Graff-Radford, NR , Boeve, BF , Dickson, DW & Rademakers, R 2016, 'TYROBP genetic variants in early-onset Alzheimer's disease', Neurobiology of aging, vol. 48, pp. 222.e9-222.e15. https://doi.org/10.1016/j.neurobiolaging.2016.07.028

@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. Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

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doi = "10.1016/j.neurobiolaging.2016.07.028",

language = "English (US)",

volume = "48",

pages = "222.e9--222.e15",

journal = "Neurobiology of Aging",

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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 - 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, Gaël Nicolas, and Anne-Claire Richard were supported by France Génomique 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. 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

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VL - 48

SP - 222.e9-222.e15

JO - Neurobiology of Aging

JF - Neurobiology of Aging

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ER -

TYROBP genetic variants in early-onset Alzheimer's disease

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Keywords

ASJC Scopus subject areas

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