Mutations modifying sporadic Alzheimer's disease age of onset
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Mutations modifying sporadic Alzheimer's disease age of onset. / 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; Easteal, Simon; Mastronardi, Claudio A; Arcos-Burgos, Mauricio.
in: AM J MED GENET B, Jahrgang 171, Nr. 8, 12.2016, S. 1116-1130.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mutations modifying sporadic Alzheimer's disease age of onset
AU - Vélez, Jorge I
AU - Lopera, Francisco
AU - Patel, Hardip R
AU - Johar, Angad S
AU - Cai, Yeping
AU - Rivera, Dora
AU - Tobón, Carlos
AU - Villegas, Andrés
AU - Sepulveda-Falla, Diego
AU - Lehmann, Shaun G
AU - Easteal, Simon
AU - Mastronardi, Claudio A
AU - Arcos-Burgos, Mauricio
N1 - © 2016 Wiley Periodicals, Inc.
PY - 2016/12
Y1 - 2016/12
N2 - 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. © 2016 Wiley Periodicals, Inc.
AB - 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. © 2016 Wiley Periodicals, Inc.
KW - Age of Onset
KW - Aged
KW - Alzheimer Disease/genetics
KW - Exome
KW - Female
KW - Genetic Predisposition to Disease/genetics
KW - Genome-Wide Association Study/methods
KW - Genotype
KW - Humans
KW - Male
KW - Middle Aged
KW - Mutation
U2 - 10.1002/ajmg.b.32493
DO - 10.1002/ajmg.b.32493
M3 - SCORING: Journal article
C2 - 27573710
VL - 171
SP - 1116
EP - 1130
JO - AM J MED GENET B
JF - AM J MED GENET B
SN - 1552-4841
IS - 8
ER -