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

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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 languageEnglish (US)
Pages (from-to)222.e9-222.e15
JournalNeurobiology of aging
StatePublished - Dec 1 2016


  • Alzheimer's disease
  • Burden test
  • Exome sequencing
  • TREM2

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology


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