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

CollaborationWith : Frisoni, Giovanni
Published in Neurobiology of Aging. 2018, vol. 66, p. 181.e3-181.e10
Abstract 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.
Keywords Adaptor Proteins, Vesicular Transport/chemistry/geneticsAgedBelgiumBinding SitesCohort StudiesEuropeFemaleGenetic Association StudiesGenetic Variation/geneticsHumansIntercellular Signaling Peptides and ProteinsMaleMiddle AgedProgranulinsProtein BindingProtein DomainsRisk
PMID: 29555433
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Research group Troubles de mémoire et maladie d'Alzeimer (935)
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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 https://archive-ouverte.unige.ch/unige:116068

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Deposited on : 2019-04-10

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