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

BELNEU Consortium

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)181.e3-181.e10
JournalNeurobiology of Aging
Publication statusPublished - Jun 2018


  • Adaptor Proteins, Vesicular Transport/chemistry
  • 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


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