A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease.

Jorge I Vélez,Yeping Cai,Simon Easteal,Carlos Tobón,Mauricio Arcos-Burgos,Dora Rivera,Francisco Lopera,Hardip R Patel,Claudio A Mastronardi,Andrés Villegas

doi:10.1155/2016/9760314

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.

Highlights

Alzheimer’s disease (AD, OMIM 104300), the most common type of dementia, is a neurodegenerative disorder characterized by learning disabilities, cognitive decline, aggression, and short- and long-term memory loss [1]
The median age of onset (AOO) of AD in these individuals is ∼49 years [95% CI 49-50], the broad spectrum of the AOO of dementia symptoms can be in the range of ∼30–80 years [13, 16]. We previously identified both known and novel loci genome-wide significantly associated with AOO in AD, including D-amino acid oxidase activator (DAOA; rs778296, P = 1.58 × 10−12), Homo sapiens CD44 molecule (CD44; rs187116, P = 1.29 × 10−12), Gremlin 2, DAN family BMP antagonist (GREM2; rs12129547, P = 1.69 × 10−13), Nephronophthisis 1 (NPHP1; rs10173717, P = 1.74 × 10−12), Homo sapiens Ca++-dependent secretion activator 2 (CADPS2; rs3757536, P = 1.54 × 10−10), Homo sapiens clusterin associated protein 1 (CLUAP1; rs1134597, P = 1.12×10−8), and Homo sapiens exocyst complex component 2 (EXOC2; rs2804737, P = 3.28 × 10−6) [18]
We found that an exonic missense mutation in the DAOA gene modifies the AOO in PSEN1 E280A AD

Summary

Introduction

Alzheimer’s disease (AD, OMIM 104300), the most common type of dementia, is a neurodegenerative disorder characterized by learning disabilities, cognitive decline, aggression, and short- and long-term memory loss [1]. Over the last 30 years, our group has studied the world’s largest multigenerational pedigree in which a mutation in the PSEN1 gene, known as the PSEN1 p.Glu280Ala E280A mutation (often referred to as the Paisa mutation), cosegregates with EOAD [2, 10]. This pedigree originated as a consequence of a founder effect [11] initially traced to 1783 [12] and localizes in a homogeneous environment [12, 13]

Methods

Results

Conclusion