ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease

Christopher W. Medway, Samer Abdul-Hay, Tynickwa Mims, Li Ma, Gina Bisceglio, Fanggeng Zou, Shane Pankratz, Sigrid B. Sando, Jan O. Aasly, Maria Barcikowska, Joanna Siuda, Zbigniew K Wszolek, Owen A Ross, Minerva M Carrasquillo, Dennis W Dickson, Neill R Graff Radford, Ronald Carl Petersen, Nilufer Taner, Kevin Morgan, Guojun D BuSteven G Younkin

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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 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.

Original languageEnglish (US)
Article number11
JournalMolecular Neurodegeneration
Volume9
Issue number1
DOIs
StatePublished - Mar 10 2014

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Apolipoproteins E
Alzheimer Disease
Exome
Alleles
Linkage Disequilibrium
Haplotypes
Costs and Cost Analysis
Genome-Wide Association Study
Risk Reduction Behavior
Single Nucleotide Polymorphism
Odds Ratio
Lipids

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

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ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. / Medway, Christopher W.; Abdul-Hay, Samer; Mims, Tynickwa; Ma, Li; Bisceglio, Gina; Zou, Fanggeng; Pankratz, Shane; Sando, Sigrid B.; Aasly, Jan O.; Barcikowska, Maria; Siuda, Joanna; Wszolek, Zbigniew K; Ross, Owen A; Carrasquillo, Minerva M; Dickson, Dennis W; Graff Radford, Neill R; Petersen, Ronald Carl; Taner, Nilufer; Morgan, Kevin; Bu, Guojun D; Younkin, Steven G.

In: Molecular Neurodegeneration, Vol. 9, No. 1, 11, 10.03.2014.

Research output: Contribution to journalArticle

Medway, Christopher W. ; Abdul-Hay, Samer ; Mims, Tynickwa ; Ma, Li ; Bisceglio, Gina ; Zou, Fanggeng ; Pankratz, Shane ; Sando, Sigrid B. ; Aasly, Jan O. ; Barcikowska, Maria ; Siuda, Joanna ; Wszolek, Zbigniew K ; Ross, Owen A ; Carrasquillo, Minerva M ; Dickson, Dennis W ; Graff Radford, Neill R ; Petersen, Ronald Carl ; Taner, Nilufer ; Morgan, Kevin ; Bu, Guojun D ; Younkin, Steven G. / ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. In: Molecular Neurodegeneration. 2014 ; Vol. 9, No. 1.
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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 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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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 M

AU - Dickson, Dennis W

AU - Graff Radford, Neill R

AU - Petersen, Ronald Carl

AU - Taner, Nilufer

AU - Morgan, Kevin

AU - Bu, Guojun D

AU - Younkin, Steven G

PY - 2014/3/10

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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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