Original Investigation

Human Genetics

, Volume 113, Issue 3, pp 258-267

First online:

Sequence variation in the CHAT locus shows no association with late-onset Alzheimer's disease

  • Denise HaroldAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
  • , Timothy PeirceAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
  • , Valentina MoskvinaAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
  • , Amanda MyersAffiliated withLaboratory of Neurogenetics, MSC 0900, Building 9, Room 1N108, National Institute of Aging, National Institute of Health
  • , Susan JonesAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
  • , Paul HollingworthAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
  • , Pamela MooreAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
  • , Simon LovestoneAffiliated withInstitute of Psychiatry
  • , John PowellAffiliated withInstitute of Psychiatry
    • , Catherine FoyAffiliated withInstitute of Psychiatry
    • , Nicola ArcherAffiliated withInstitute of Psychiatry
    • , Sarah WalterAffiliated withInstitute of Psychiatry
    • , Amanda EdmonsonAffiliated withInstitute of Psychiatry
    • , Stephen McIlroyAffiliated withDepartment of Geriatric Medicine, Queen's University Belfast
    • , David CraigAffiliated withDepartment of Geriatric Medicine, Queen's University Belfast
    • , Peter A. PassmoreAffiliated withDepartment of Geriatric Medicine, Queen's University Belfast
    • , Alison GoateAffiliated withDepartments of Psychiatry and Neurology, Washington University School of Medicine
    • , John HardyAffiliated withLaboratory of Neurogenetics, MSC 0900, Building 9, Room 1N108, National Institute of Aging, National Institute of Health
    • , Michael O'DonovanAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
    • , Julie WilliamsAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
    • , Malcolm LiddellAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
    • , Michael J. OwenAffiliated withDepartment of Psychological Medicine, University of Wales College of Medicine
    • , Lesley JonesAffiliated withDepartment of Psychological Medicine, University of Wales College of MedicineInstitute of Medical Genetics, University of Wales College of Medicine Email author 

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Abstract

There is substantial evidence for a susceptibility gene for late-onset Alzheimer's disease (AD) on chromosome 10. One of the characteristic features of AD is the degeneration and dysfunction of the cholinergic system. The genes encoding choline acetyltransferase (ChAT) and its vesicular transporter (VAChT), CHAT and SLC18A3 respectively, map to the linked region of chromosome 10 and are therefore both positional and obvious functional candidate genes for late-onset AD. We have screened both genes for sequence variants and investigated each for association with late-onset AD in up to 500 late-onset AD cases and 500 control DNAs collected in the UK. We detected a total of 17 sequence variants. Of these, 14 were in CHAT, comprising three non-synonymous variants (D7N in the S exon, A120T in exon 5 and L243F in exon 8), one synonymous change (H547H), nine single-nucleotide polymorphisms in intronic, untranslated or promoter regions, and a variable number of tandem repeats in intron 7. Three non-coding SNPs were detected in SLC18A3. None demonstrated any reproducible association with late-onset AD in our samples. Levels of linkage disequilibrium were generally low across the CHAT locus but two of the coding variants, D7N and A120T, proved to be in complete linkage disequilibrium.