Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Neurobiol Aging. 2018 Feb;62:245.e1-245.e7. doi: 10.1016/j.neurobiolaging.2017.10.012. Epub 2017 Oct 25.

Abstract

TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13-1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.

Keywords: Early onset Alzheimer's disease; Frontotemporal dementia; Loss-of-function; RNA sequencing; TBK1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Alleles
  • Alzheimer Disease / genetics*
  • Amyotrophic Lateral Sclerosis / genetics
  • Cohort Studies
  • Europe
  • Female
  • Frontotemporal Dementia / genetics
  • Genetic Association Studies*
  • Genetic Variation / genetics*
  • Heterozygote
  • Homozygote
  • Humans
  • Loss of Function Mutation / genetics*
  • Male
  • Middle Aged
  • Protein-Serine-Threonine Kinases / genetics*
  • Risk

Substances

  • Protein-Serine-Threonine Kinases
  • TBK1 protein, human