Scientific article
Open access

Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia

ContributorsBELNEU Consortium; EU EOD Consortium
CollaboratorsFrisoni, Giovanni
Published inNeurobiology of Aging, vol. 66, p. 181.e3-181.e10
Publication date2018

We investigated the genetic role of sortilin (SORT1) in frontotemporal dementia (FTD). SORT1 is the neuronal receptor for granulin, encoded by the progranulin gene (GRN), a major causal gene for inherited FTD. In Belgian cohorts of 636 FTD patients and 1066 unaffected control individuals, we identified 5 patient-only nonsynonymous rare variants in SORT1. Rare variant burden analysis showed a significant increase in rare coding variants in patients compared to control individuals (p = 0.04), particularly in the β-propeller domain (p = 0.04), with 2 rare variants located in the predicted binding site for GRN (p = 0.001). We extended these observations by analyzing 3 independent patient/control cohorts sampled in Spain, Italy, and Portugal by partners of the European Early-Onset Dementia Consortium, together with 1155 FTD patients and 1161 control persons. An additional 7 patient-only nonsynonymous variants were observed in SORT1 in European patients. Meta-analysis of the rare nonsynonymous variants in the Belgian and European patient/control cohorts revealed a significant enrichment in FTD patients (p = 0.006), establishing SORT1 as a genetic risk factor for FTD.

  • Adaptor Proteins, Vesicular Transport/chemistry/genetics
  • Aged
  • Belgium
  • Binding Sites
  • Cohort Studies
  • Europe
  • Female
  • Genetic Association Studies
  • Genetic Variation/genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Progranulins
  • Protein Binding
  • Protein Domains
  • Risk
Citation (ISO format)
BELNEU Consortium, EU EOD Consortium. Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia. In: Neurobiology of Aging, 2018, vol. 66, p. 181.e3–181.e10. doi: 10.1016/j.neurobiolaging.2018.02.011
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Article (Published version)
ISSN of the journal0197-4580

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