Original Investigation

Human Genetics

, Volume 109, Issue 6, pp 646-652

Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease

  • Richard AbrahamAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
  • , Amanda MyersAffiliated withDepartments of Psychiatry and Neurology, Washington University School of Medicine, 660 S Euclid, St. Louis, MO 63110, USA
  • , Fabienne Wavrant-DeVriezeAffiliated withLaboratory for Neurogenetics, Birdsall Building, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA
  • , Marian L. HamshereAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
  • , Hollie V. ThomasAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
  • , Helen MarshallAffiliated withDepartments of Psychiatry and Neurology, Washington University School of Medicine, 660 S Euclid, St. Louis, MO 63110, USA
  • , Danielle ComptonAffiliated withLaboratory for Neurogenetics, Birdsall Building, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA
  • , Gillian SpurlockAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
  • , Dragana TuricAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
    • , Bastiaan HoogendoornAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
    • , Jennifer M. KwonAffiliated withDepartments of Psychiatry and Neurology, Washington University School of Medicine, 660 S Euclid, St. Louis, MO 63110, USA
    • , Ronald C. PetersenAffiliated withDepartments of Neurology and General Medicine, Mayo Clinic, Rochester, MN55905, USA
    • , Eric TangalosAffiliated withDepartments of Neurology and General Medicine, Mayo Clinic, Rochester, MN55905, USA
    • , Joanne NortonAffiliated withDepartments of Psychiatry and Neurology, Washington University School of Medicine, 660 S Euclid, St. Louis, MO 63110, USA
    • , John C. MorrisAffiliated withDepartments of Psychiatry and Neurology, Washington University School of Medicine, 660 S Euclid, St. Louis, MO 63110, USA
    • , Roger BullockAffiliated withDepartment of Old Age Psychiatry, Victoria Hospital, Okus Road, Swindon SN1 4JU, UK
    • , Danae LiolitsaAffiliated withInstitute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
    • , Simon LovestoneAffiliated withInstitute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK
    • , John HardyAffiliated withLaboratory for Neurogenetics, Birdsall Building, Mayo Clinic Jacksonville, Jacksonville FL 32224, USA
    • , Alison GoateAffiliated withDepartments of Psychiatry and Neurology, Washington University School of Medicine, 660 S Euclid, St. Louis, MO 63110, USA
    • , Michael O'DonovanAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
    • , Julie WilliamsAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
    • , Michael J. OwenAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK
    • , Lesley JonesAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine, Cardiff CF14 4XN, UK

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract.

Insulin-degrading enzyme (IDE; insulysin; EC 3.4.24.56) is a 110-kDa neutral metallopeptidase that can degrade a number of peptides including β-amyloid. The gene encoding IDE is located on chromosome 10 close to a region of linkage for late-onset Alzheimer's disease (LOAD) and thus is a functional and positional candidate for this disorder. We analysed all of the coding exons, untranslated regions and 1000 bp of 5′-flanking sequence of IDE by using denaturing high-performance liquid chromatography and sequencing. We detected eight single nucleotide polymorphisms (SNPs), three in the 5′ flanking sequence and five in the coding sequence, of which three were found at lower than 5% frequency. None of them changed the amino acid sequence. We genotyped the five SNPs with allele frequencies of more than 5% in 133 Caucasian LOAD cases and 135 controls collected in the UK and 95 cases and 117 controls collected at the Mayo Clinic, Rochester, USA. Two of the SNPs were analysed in a further independent case-control sample (Washington University, St. Louis: 86 cases, 94 controls). No significant association was found with any individual SNP in any of the samples or with any haplotypes. Analysis of the marker D10S583, which maps 36 kb upstream of IDE, also failed to show association in 134 cases and 111 matched controls from the UK (P=0.63). Strong linkage disequilibrium was detected between the five SNPs that spanned the whole of the 120-kb genomic region of IDE and one major and a number of minor haplotypes were detected in the populations studied. We conclude that IDE does not make a substantial contribution to the aetiology of LOAD and therefore cannot account for the linkage between LOAD and 10q.