By analyzing late onset Alzheimer's disease (LOAD) in a genome wide association study (313,504 SNPs, 3 series, 844 cases/1,255 controls) and evaluating the 25 SNPs with most significant allelic association in 4 additional series (1,547 cases/1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in American Caucasians. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7×10 -5 in stage I, 4.8×10 -6 in stage II, and 3.9×10 -12 in the combined data. Odds ratios were 1.75 (95% CI 1.42-2.16) for female homozygotes (P=2.0×10 -7 ) and 1.26 (95% CI 1.05-1.51) for female heterozygotes (P=0.01) compared to female non-carriers. For male hemizygotes (P=0.07) compared to male non-carriers the odds ratio was 1.18 (95% CI 0.99-1.41).Late onset Alzheimer's disease (LOAD) is a neurodegenerative disease characterized by large numbers of senile plaques and neurofibrillary tangles in the brain. LOAD is the most common cause of dementia in the elderly, affecting approximately 10% of those aged 65 years or older 1 . Multiple rare mutations in the genes encoding the amyloid ß protein precursor, presenilin 1, and presenilin 2 cause an early onset familial form of AD with autosomal dominant inheritance, but the only well established susceptibility allele for LOAD is the APOE ε4, To whom correspondence should be address: younkin.steven@mayo.edu. Author Contributions: M.M.C. spearheaded and participated in all aspects of this study, and drafted the manuscript along with Steven G. Younkin who is the lead investigator of this study. F.Z., S.L.W., L.M. and L.P.W. participated in the SEQUENOM genotyping. F.Z., L.M., L.H.Y. and G.D.B. were responsible for DNA sample preparation and quality control. L.M. also generated all DNA replica plates. Samuel G. Younkin and C.S.Y were instrumental in data management and analysis. N.E.T. participated in critical revisions of the manuscript. V.S.P and J.E.C. provided statistical expertise. N.R.G. and R.C.P. are the neurologists who diagnosed and provided samples for the Mayo Clinic Jacksonville (JS) and Mayo Clinic Rochester (RS) series, respectively. D.W.D. is the pathologist who diagnosed and provided brain samples for the autopsy-confirmed (AUT) series.URLs. PLINK, http://pngu.mgh.harvard.edu/purcell/plink/ Accession codes. RefSeq: PCDH11X mRNA isoform a precursor, NM_014522.1; PCDH11X mRNA isoform b precursor, NM_032967.1; PCDH11X mRNA isoform c, NM_032968.2; PCDH11X mRNA isoform d precursor, NM_032969.2. Entrez Gene: PCDH11X, 27328; PCDH11Y, 83259. sexually dimorphic traits 9 . To explore this possibility, we analyzed rs5984894 by multivariable logistic regression with sex as a covariate (Table 2). Using this approach, which specifically models each carrier group, the global P value in the combined series improved substantially to 3.9×10 -12 as compared to 3.8×10 -8 for allelic association (Supplementary Table 3) and 2.2×10 -7 using the Mantel-Haenszel method (Table 1). In the combined se...

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.

Glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) and its paralogues were implicated in late-onset Alzheimer's disease (LOAD), although the strength and direction of association have not been consistent. We genotyped three previously reported SNPs (rs3741916-GAPDH 5'UTR, rs2029721-pGAPD and rs4806173-GAPDHS) in three case-control series (2112 cases and 3808 controls). Rs3741916 showed the strongest LOAD association (p=0.003). The minor allele of rs3741916 showed a protective effect in our combined series (OR=0.87, 95% confidence interval (CI)=0.79-0.96). This is consistent with results from the two published follow-up studies and in © 2010 Elsevier Inc. All rights reserved. # To whom correspondence should be address: taner.nilufer@mayo.edu or younkin.steven@mayo.edu, ). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Figure A and Supplemental Data Information: Supplementary Text, Search Terms