Ítem
Solo Metadatos
Mutations modifying sporadic Alzheimer's disease age of onset
Título de la revista
Autores
Vélez, Jorge I.
Lopera, Francisco
Patel, Hardip R.
Johar, Angad S.
Cai, Yeping
Rivera, Dora
Tobón, Carlos
Villegas ,Andrés
Sepulveda-Falla, Diego
Lehmann, Shaun G.
Fecha
2016-08-30
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Editor
John Wiley and Sons
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Resumen
Abstract
The identification of mutations modifying the age of onset (AOO) in Alzheimer's disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole-exome genotyped. Single- and multi-locus linear mixed-effects models were used to identify functional variants modifying AOO. A posteriori enrichment and bioinformatic analyses were applied to evaluate the non-random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome-wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. This set of new genes harboring these mutations could be of importance for prediction, follow-up and eventually as therapeutical targets of AD.
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Keywords
Alzheimer's disease , E280A mutation , G protein-coupled receptors , PSEN1 , Age of onset , Extreme phenotypes , Genetic isolates , Modifier genes , Whole exome analysis
