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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.

A Mutation inDAOAModifies the Age of Onset inPSEN1E280A Alzheimer’s Disease