Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme

Petra Nowotny, Anthony L. Hinrichs, Scott Smemo, John S.K. Kauwe, Taylor Maxwell, Peter Holmans, Marian Hamshere, Dragana Turic, Luke Jehu, Paul Hollingworth, Pamela Moore, Leslie Bryden, Amanda Myers, Lisa M. Doil, Kristina M. Tacey, Alison M. Gibson, Ian G. McKeith, Robert H. Perry, Chris M. Morris, Leon ThalJohn C. Morris, Michael C. O'Donovan, Simon Lovestone, Andrew Grupe, John Hardy, Michael J. Owen, Julie Williams, Alison Goate

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Abstract

Linkage studies have suggested there is a susceptibility gene for late onset Alzheimer's disease (LOAD) in a broad region of chromosome 10. A strong positional and biological candidate is the gene encoding the insulin-degrading enzyme (IDE), a protease involved in the catabolism of Aβ. However, previous association studies have produced inconsistent results. To systematically evaluate the role of variation in IDE in the risk for LOAD, we genotyped 18 SNPs spanning a 276 kb region in and around IDE, including three "tagging" SNPs identified in an earlier study. We used four case-control series with a total of 1,217 cases and 1,257 controls. One SNP (IDE_7) showed association in two samples (P-value = 0.0066, and P = 0.026, respectively), but this result was not replicated in the other two series. None of the other SNPs showed association with LOAD in any of the tested samples. Haplotypes, constructed from the three tagging SNPs, showed no globally significant association. In the UK2 series, the CTA haplotype was over-represented in cases (P = 0.046), and in the combined data set, the CCG haplotype was more frequent in controls (P = 0.015). However, these weak associations observed in our series were in the opposite direction to the results in previous studies. Although our results are not universally negative, we were unable to replicate the results of previous studies and conclude that common variants or haplotypes of these variants in IDE are not major risk factors for LOAD.

Original languageEnglish
Pages (from-to)62-68
Number of pages7
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume136 B
Issue number1
DOIs
StatePublished - Jul 5 2005

Keywords

  • Association studies
  • Haplotype
  • IDE
  • Load
  • SNP

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    Nowotny, P., Hinrichs, A. L., Smemo, S., Kauwe, J. S. K., Maxwell, T., Holmans, P., Hamshere, M., Turic, D., Jehu, L., Hollingworth, P., Moore, P., Bryden, L., Myers, A., Doil, L. M., Tacey, K. M., Gibson, A. M., McKeith, I. G., Perry, R. H., Morris, C. M., ... Goate, A. (2005). Association studies between risk for late-onset Alzheimer's disease and variants in insulin degrading enzyme. American Journal of Medical Genetics - Neuropsychiatric Genetics, 136 B(1), 62-68. https://doi.org/10.1002/ajmg.b.30186