A Mutation inDAOAModifies the Age of Onset inPSEN1E280A 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 thePSEN1gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals withPSEN1E280A 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 theG72(DAOA) gene (rs2391191,P= 1.94 × 10−4,PFDR= 9.34 × 10−3) was found to modify AOO inPSEN1E280A AD. Nominal associations of missense mutations in theCLUAP1(rs9790,P= 7.63 × 10−3,PFDR= 0.1832) andEXOC2(rs17136239,P= 0.0325,PFDR= 0.391) genes were also found. Previous studies have linked polymorphisms in theDAOAgene 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 theG72(DAOA) gene could be pivotal for understanding the genetic basis of AD.