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

Nature Genetics volume 41, pages 192–198 (2009)Cite this article

Abstract

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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NCBI Reference Sequence

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Acknowledgements

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

  1. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, 32224, Florida, USA

    Minerva M Carrasquillo, Fanggeng Zou, Samantha L Wilcox, Li Ma, Louise P Walker, Samuel G Younkin, Curtis S Younkin, Linda H Younkin, Gina D Bisceglio, Nilufer Ertekin-Taner, Dennis W Dickson, Neill R Graff-Radford & Steven G Younkin

  2. Division of Biomedical Statistics and Informatics, Mayo Clinic and Mayo Foundation, Rochester, 55905, Minnesota, USA

    V Shane Pankratz

  3. Department of Neurology, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Nilufer Ertekin-Taner, Ronald C Petersen & Neill R Graff-Radford

  4. Biostatistics Unit, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Julia E Crook

  5. Mayo Alzheimer Disease Research Center, Mayo Clinic College of Medicine, Rochester, 55905, Minnesota, USA

    Ronald C Petersen

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  1. Minerva M Carrasquillo
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  2. Fanggeng Zou
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  16. Steven G Younkin
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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.-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.

Corresponding author

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). https://doi.org/10.1038/ng.305

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