title: Mutations modifying sporadic Alzheimer's disease age of onset.
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. © 2016 Wiley Periodicals, Inc.
authors: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.|Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors: Jorge I
authors: JI
authors: Vélez
authors: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors: Francisco
authors: F
authors: Lopera
authors: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Hardip R
authors: HR
authors: Patel
authors: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Angad S
authors: AS
authors: Johar
authors: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Yeping
authors: Y
authors: Cai
authors: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors: Dora
authors: D
authors: Rivera
authors: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors: Carlos
authors: C
authors: Tobón
authors: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors: Andrés
authors: A
authors: Villegas
authors: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.|Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors: Diego
authors: D
authors: Sepulveda-Falla
authors: Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Shaun G
authors: SG
authors: Lehmann
authors: Genome Diversity and Health Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Simon
authors: S
authors: Easteal
authors: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
authors: Claudio A
authors: CA
authors: Mastronardi
authors: Genomics and Predictive Medicine Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.|Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors: Mauricio
authors: M
authors: Arcos-Burgos
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation
keywords: Alzheimer's disease; E280A mutation; G protein-coupled receptors; PSEN1; age of onset; extreme phenotypes; genetic isolates; modifier genes; whole exome analysis