TY - JOUR
T1 - ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease
AU - Medway, Christopher W.
AU - Abdul-Hay, Samer
AU - Mims, Tynickwa
AU - Ma, Li
AU - Bisceglio, Gina
AU - Zou, Fanggeng
AU - Pankratz, Shane
AU - Sando, Sigrid B.
AU - Aasly, Jan O.
AU - Barcikowska, Maria
AU - Siuda, Joanna
AU - Wszolek, Zbigniew K.
AU - Ross, Owen A.
AU - Carrasquillo, Minerva
AU - Dickson, Dennis W.
AU - Graff-Radford, Neill
AU - Petersen, Ronald C.
AU - Ertekin-Taner, Nilüfer
AU - Morgan, Kevin
AU - Bu, Guojun
AU - Younkin, Steven G.
N1 - Funding Information:
We would like to thank the patients and their families who participated in this research. Supported by NIH grants; R01 AG032990 (NET), P50 AG016574 (RP/NET/SGY), R01 NS080820 (NET), U01 AG046139 (NET/SGY), R01 AG18023 (SGY), R01 AG035355 (GB), R01 AG027924 (GB), R01 AG046205 (GB). CWM is funded by an Alzheimer’s Research UK US travel fellowship and the Sir Terry Pratchett Prize. JS is supported by the Stowarzyszenie na Rzecz Rozwoju Neurologii Wieku Podeszlego grant. ZKW is partially supported by the NIH/ NINDS P50 NS072187, The Michael J. Fox Foundation for Parkinson’s Research, and the gift from Carl Edward Bolch, Jr., and Susan Bass Bolch.
PY - 2014/3/10
Y1 - 2014/3/10
N2 - 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 4 allele, showed no association with LOAD (P = 0.75) independent of the APOE 4 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 3 allele, identifies a novel LOAD-associated haplotype (APOE 3b) which is associated with decreased risk of LOAD independent of the more abundant APOE 2, 3 and 4 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.
AB - 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 4 allele, showed no association with LOAD (P = 0.75) independent of the APOE 4 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 3 allele, identifies a novel LOAD-associated haplotype (APOE 3b) which is associated with decreased risk of LOAD independent of the more abundant APOE 2, 3 and 4 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.
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U2 - 10.1186/1750-1326-9-11
DO - 10.1186/1750-1326-9-11
M3 - Article
C2 - 24607147
AN - SCOPUS:84899116901
SN - 1750-1326
VL - 9
JO - Molecular neurodegeneration
JF - Molecular neurodegeneration
IS - 1
M1 - 11
ER -