title: ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease.
abstract: Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these "actionable" variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D' = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5 × 10⁻⁰⁵; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D' = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Medway
authors.forename: Samer
authors.initials: S
authors.lastname: Abdul-Hay
authors.forename: Tynickwa
authors.initials: T
authors.lastname: Mims
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Gina
authors.initials: G
authors.lastname: Bisceglio
authors.forename: Fanggeng
authors.initials: F
authors.lastname: Zou
authors.forename: Shane
authors.initials: S
authors.lastname: Pankratz
authors.forename: Sigrid B
authors.initials: SB
authors.lastname: Sando
authors.forename: Jan O
authors.initials: JO
authors.lastname: Aasly
authors.forename: Maria
authors.initials: M
authors.lastname: Barcikowska
authors.forename: Joanna
authors.initials: J
authors.lastname: Siuda
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.forename: Minerva
authors.initials: M
authors.lastname: Carrasquillo
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Neill
authors.initials: N
authors.lastname: Graff-Radford
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Nilüfer
authors.initials: N
authors.lastname: Ertekin-Taner
authors.forename: Kevin
authors.initials: K
authors.lastname: Morgan
authors.affiliation: Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA. bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
mesh_terms: D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D001057:Apolipoproteins E