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Title
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Rare nonsynonymous variants in SORT1 are associated with increased risk for frontotemporal dementia
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Author
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Institution/Organisation
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BELNEU Consortium
EU EOD Consortium
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Abstract
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| 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. |
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Language
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Dutch, English
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Source (journal)
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Neurobiology of aging. - Fayetteville, N.Y.
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Publication
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Fayetteville, N.Y.
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2018
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ISSN
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0197-4580
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DOI
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10.1016/J.NEUROBIOLAGING.2018.02.011
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Volume/pages
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66
(2018)
, 8 p.
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Article Reference
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181.e3
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ISI
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000431006300031
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Pubmed ID
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29555433
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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