Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease

Peter Holmans, Marian Hamshere, Paul Hollingworth, Frances Rice, Nigel Tunstall, Sue Jones, Pamela Moore, Fabienne Wavrant DeVrieze, Amanda Hyers, Richard Crook, Danielle Compton, Helen Marshall, David Meyer, Shantia Shears, Jeremy Booth, Bzanan Ramic, Nigel Williams, Nadine Norton, Richard Abraham, Pat KehoeHywel Williams, Varuni Rudrasingham, Mick O'Donovan, Lesley Jones, John Hardy, Alison Goate, Simon Lovestone, Michael Owen, Julie Williams

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the MMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the MMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE ε4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.

Original languageEnglish (US)
Pages (from-to)24-32
Number of pages9
JournalAmerican Journal of Medical Genetics - Neuropsychiatric Genetics
Volume135 B
Issue number1
DOIs
StatePublished - May 5 2005

Keywords

  • Age at onset
  • Alzheimer's Disease
  • Genome screen
  • Linkage
  • Rate of decline

ASJC Scopus subject areas

  • Genetics(clinical)
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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    Holmans, P., Hamshere, M., Hollingworth, P., Rice, F., Tunstall, N., Jones, S., Moore, P., Wavrant DeVrieze, F., Hyers, A., Crook, R., Compton, D., Marshall, H., Meyer, D., Shears, S., Booth, J., Ramic, B., Williams, N., Norton, N., Abraham, R., ... Williams, J. (2005). Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease. American Journal of Medical Genetics - Neuropsychiatric Genetics, 135 B(1), 24-32. https://doi.org/10.1002/ajmg.b.30114