Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease

Abstract

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...

Kinesin Light Chain 1 Gene Haplotypes in Three Conformational Diseases

“…In the second study, performed by our group, we failed to replicate this finding, although we did find an association between the C allele of rs8702 and increased P-tau 181 CSF levels in patients with incipient AD (Andersson et al 2007a). Several genome-wide association studies of AD have been reported but have not identified any association of KLC1 with AD (Coon et al 2007;Grupe et al 2007;Reiman et al 2007;Abraham et al 2008;Bertram et al 2008;Li et al 2008;Beecham et al 2009;Carrasquillo et al 2009;Harold et al 2009;Lambert et al 2009;Poduslo et al 2009;Potkin et al 2009). Altogether, the rather weak single SNP associations with AD in this and the previous study reporting association with KLC1, lack of association in the genome-wide association studies, the somewhat contradicting result of rs3212079, and the lack of strengthened association upon haplotype analysis, implies that the observed associations may be a result of type I error rather than a true association of KLC1 with AD.…”

Copy number variants on the X chromosome in women with primary ovarian insufficiency

“…The PCDH11X (protocadherin 11 X-linked) gene has scarcely been investigated; a polymorphism in this gene has been linked to Alzheimer disease (27,28). The TGIF2LX (TGFB-induced factor homeobox 2-like, X-linked) gene is associated with male infertility and may be required for the regulation of spermatogonial stem cell specification and proliferation, but its role in females is not clear (29).…”

Genetics of Alzheimer's disease: new evidences for an old hypothesis?

“…Between 2007 and 2009, several genome-wide association studies (GWASs) in AD were performed with low numbers of cases and controls (less than 1000 per group), limiting their relevance for such a complex disease [11][12][13][14][15][16]. However, since then, several powerful GWASs have been recently published, suddenly improving our knowledge of the AD genetics.…”