title: Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.
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 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.
authors.affiliation: Biostatistics and Bioinformatics Unit, Wales College of Medicine, Heath Park, Cardiff, United Kingdom. holmanspa@cardiff.ac.uk
authors.forename: Peter
authors.initials: P
authors.lastname: Holmans
authors.forename: Marian
authors.initials: M
authors.lastname: Hamshere
authors.forename: Paul
authors.initials: P
authors.lastname: Hollingworth
authors.forename: Frances
authors.initials: F
authors.lastname: Rice
authors.forename: Nigel
authors.initials: N
authors.lastname: Tunstall
authors.forename: Sue
authors.initials: S
authors.lastname: Jones
authors.forename: Pamela
authors.initials: P
authors.lastname: Moore
authors.forename: Fabienne
authors.initials: F
authors.lastname: Wavrant DeVrieze
authors.forename: Amanda
authors.initials: A
authors.lastname: Myers
authors.forename: Richard
authors.initials: R
authors.lastname: Crook
authors.forename: Danielle
authors.initials: D
authors.lastname: Compton
authors.forename: Helen
authors.initials: H
authors.lastname: Marshall
authors.forename: David
authors.initials: D
authors.lastname: Meyer
authors.forename: Shantia
authors.initials: S
authors.lastname: Shears
authors.forename: Jeremy
authors.initials: J
authors.lastname: Booth
authors.forename: Dzanan
authors.initials: D
authors.lastname: Ramic
authors.forename: Nigel
authors.initials: N
authors.lastname: Williams
authors.forename: Nadine
authors.initials: N
authors.lastname: Norton
authors.forename: Richard
authors.initials: R
authors.lastname: Abraham
authors.forename: Pat
authors.initials: P
authors.lastname: Kehoe
authors.forename: Hywel
authors.initials: H
authors.lastname: Williams
authors.forename: Varuni
authors.initials: V
authors.lastname: Rudrasingham
authors.forename: Mick
authors.initials: M
authors.lastname: O'Donovan
authors.forename: Lesley
authors.initials: L
authors.lastname: Jones
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Michael
authors.initials: M
authors.lastname: Owen
authors.forename: Julie
authors.initials: J
authors.lastname: Williams
mesh_terms: D017668:Age of Onset; D000544:Alzheimer Disease / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D002874:Chromosome Mapping; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D008126:Lod Score; D035781:Siblings
chemical_list: D001057:Apolipoproteins E