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

Holmans, Peter Alan ORCID:, Hamshere, Marian Lindsay ORCID:, Hollingworth, P., Rice, Frances ORCID:, Tunstall, N., Jones, S., Moore, P., Wavrant DeVrieze, F., Myers, A., Crook, R., Compton, D., Marshall, H., Meyer, D., Shears, S., Booth, J., Ramic, D., Williams, Nigel Melville ORCID:, Norton, N., Abraham, R., Kehoe, P., Williams, H., Rudrasingham, V., O'Donovan, Michael Conlon ORCID:, Jones, Lesley ORCID:, Hardy, J., Goate, A., Lovestone, S., Owen, Michael John ORCID: and Williams, Julie ORCID: 2005. Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 135B (1) , pp. 24-32. 10.1002/ajmg.b.30114

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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 NIMH 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 NIMH 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 epsilon4 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Neuroscience and Mental Health Research Institute (NMHRI)
Subjects: R Medicine > R Medicine (General)
Publisher: Wiley-Blackwell
ISSN: 1552-4841
Last Modified: 04 Mar 2023 03:04

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