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.
Highlights
The international effort to catalog common variants [minor allele frequency (MAF) > 5%] in the human genome (HapMap Project [1]) paved the way for genome-wide association studies (GWAS), which have proven to be a powerful tool for understanding the genetics of complex diseases
In African Americans, the MAF for rs769455 on the Exome Variant Server (EVS) is 1.39% as compared to 0.026% in European Americans, so we evaluated this variant in our African American late-onset Alzheimer’s disease (LOAD) case control series of 168 LOAD patients and 333 non-demented control subjects
To determine whether APOE ε3b or ε4b are significantly associated with LOAD independent of the ε2, ε3, and ε4 alleles, we performed multivariate logistic regression using a model that included sex and age at diagnosis as covariates and the APOE ε4 and ε2 alleles, with ε3a as referent (Table 2)
Summary
The international effort to catalog common variants [minor allele frequency (MAF) > 5%] in the human genome (HapMap Project [1]) paved the way for genome-wide association studies (GWAS), which have proven to be a powerful tool for understanding the genetics of complex diseases. To evaluate the utility of this approach, we searched the EVS for proteinaltering APOE variants with MAF > 0.1% and found just two, p.L28P (0.17%) and p.V236E (0.12%) in European Americans. Both were analyzed in our large European American case control series of 4128 LOAD subjects and 4986 non-demented controls (Table 1). In addition we analyzed one extremely rare variant, p.R145C (0.026%), that did have a MAF > 1% in African Americans
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