title: A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease.
abstract: We previously reported age of onset (AOO) modifier genes in the world's largest pedigree segregating early-onset Alzheimer's disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10(-4), P FDR = 9.34 × 10(-3)) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10(-3), P FDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, P FDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD.
authors.affiliation: The Arcos-Burgos Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia; Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: Jorge I
authors.initials: JI
authors.lastname: Vélez
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: Dora
authors.initials: D
authors.lastname: Rivera
authors.affiliation: The Arcos-Burgos Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Claudio A
authors.initials: CA
authors.lastname: Mastronardi
authors.affiliation: The Arcos-Burgos Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Hardip R
authors.initials: HR
authors.lastname: Patel
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: Carlos
authors.initials: C
authors.lastname: Tobón
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: Andrés
authors.initials: A
authors.lastname: Villegas
authors.affiliation: The Arcos-Burgos Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Yeping
authors.initials: Y
authors.lastname: Cai
authors.affiliation: The Easteal Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Easteal
authors.affiliation: Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: Francisco
authors.identifier: 0000-0003-3986-1484
authors.initials: F
authors.lastname: Lopera
authors.affiliation: The Arcos-Burgos Group, Department of Genome Sciences, John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia; Neuroscience Research Group, University of Antioquia, Medellín, Colombia.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Arcos-Burgos
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D020125:Mutation, Missense; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; D047908:Intracellular Signaling Peptides and Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1