TYROBP genetic variants in early-onset Alzheimer's disease

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Adult
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / genetics*
  • Cohort Studies
  • Down-Regulation / genetics
  • Exome / genetics
  • Female
  • Gene Expression / genetics
  • Genetic Association Studies*
  • Genetic Variation / genetics*
  • HeLa Cells
  • Humans
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation / genetics
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism
  • Sequence Analysis


  • Adaptor Proteins, Signal Transducing
  • Membrane Glycoproteins
  • Membrane Proteins
  • Receptors, Immunologic
  • TREM2 protein, human
  • TYROBP protein, human