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


By analyzing late-onset Alzheimer's disease (LOAD) in a genome-wide association study (313,504 SNPs, three series, 844 cases and 1,255 controls) and evaluating the 25 SNPs with the most significant allelic association in four additional series (1,547 cases and 1,209 controls), we identified a SNP (rs5984894) on Xq21.3 in PCDH11X that is strongly associated with LOAD in individuals of European descent from the United States. Analysis of rs5984894 by multivariable logistic regression adjusted for sex gave global P values of 5.7 × 10−5 in stage 1, 4.8 × 10−6 in stage 2 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 noncarriers. For male hemizygotes (P = 0.07) compared to male noncarriers, the odds ratio was 1.18 (95% CI = 0.99–1.41).

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Figure 1: Schematic overview of PCDH11X and LD plot showing PCDH11X haplotype blocks.

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  1. Evans, D.A. et al. Prevalence of Alzheimer's disease in a community population of older persons. Higher than previously reported. J. Am. Med. Assoc. 262, 2551–2556 (1989).

    Article  CAS  Google Scholar 

  2. Corder, E.H. et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261, 921–923 (1993).

    Article  CAS  PubMed  Google Scholar 

  3. Corder, E.H. et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat. Genet. 7, 180–184 (1994).

    Article  CAS  PubMed  Google Scholar 

  4. Farrer, L.A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. J. Am. Med. Assoc. 278, 1349–1356 (1997).

    Article  CAS  Google Scholar 

  5. Gatz, M. et al. Role of genes and environments for explaining Alzheimer disease. Arch. Gen. Psychiatry 63, 168–174 (2006).

    Article  PubMed  Google Scholar 

  6. Purcell, S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Price, A.L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006).

    Article  CAS  PubMed  Google Scholar 

  8. Williams, N.A., Close, J.P., Giouzeli, M. & Crow, T.J. Accelerated evolution of protocadherin11X/Y: a candidate gene-pair for cerebral asymmetry and language. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 623–633 (2006).

    Article  Google Scholar 

  9. Lopes, A.M. et al. Inactivation status of PCDH11X: sexual dimorphisms in gene expression levels in brain. Hum. Genet. 119, 267–275 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Durand, C.M. et al. Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 141, 67–70 (2006).

    Article  PubMed Central  Google Scholar 

  11. Blanco, P., Sargent, C.A., Boucher, C.A., Mitchell, M. & Affara, N.A. Conservation of PCDHX in mammals; expression of human X/Y genes predominantly in brain. Mamm. Genome 11, 906–914 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Blanco-Arias, P., Sargent, C.A. & Affara, N.A., Protocadherin X (PCDHX) and Y (PCDHY) genes; multiple mRNA isoforms encoding variant signal peptides and cytoplasmic domains. Mamm. Genome 15, 41–52 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Senzaki, K., Ogawa, M. & Yagi, T. Proteins of the CNR family are multiple receptors for Reelin. Cell 99, 635–647 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Haas, I.G., Frank, M., Veron, N. & Kemler, R. Presenilin-dependent processing and nuclear function of gamma-protocadherins. J. Biol. Chem. 280, 9313–9319 (2005).

    Article  CAS  PubMed  Google Scholar 

  15. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    Article  CAS  PubMed  Google Scholar 

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Support for this research was provided by grants from the US National Institutes of Health, NIA R01 AG18023 (N.R.G.-R., Steven G. Younkin); Mayo Alzheimer's Disease Research Center, P50 AG16574 (R.C.P., D.W.D., N.R.G.-R., Steven G. Younkin); Mayo Alzheimer's Disease Patient Registry, U01 AG06576 (R.C.P.); and US National Institute on Aging, AG25711, AG17216, AG03949 (D.W.D.). Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. We thank contributors, including the Alzheimer's disease centers who collected samples used in this study, as well as subjects and their families, whose help and participation made this work possible. This project was also generously supported by the Robert and Clarice Smith Postdoctoral Fellowship (M.M.C.); Robert and Clarice Smith and Abigail Van Buren Alzheimer's Disease Research Program (R.C.P., D.W.D., N.R.G.-R.; Steven G. Younkin) and by the Palumbo Professorship in Alzheimer's Disease Research (Steven G. Younkin).

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Authors and Affiliations



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.-R. 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.

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Correspondence to Steven G Younkin.

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Supplementary Tables 1–6, Supplementary Figure 1 and Supplementary Methods (PDF 426 kb)

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Carrasquillo, M., Zou, F., Pankratz, V. et al. Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease. Nat Genet 41, 192–198 (2009).

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