Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.
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.
Holmans
Peter
P
Biostatistics and Bioinformatics Unit, Wales College of Medicine, Heath Park, Cardiff, United Kingdom. holmanspa@cardiff.ac.uk
Hamshere
Marian
M
Hollingworth
Paul
P
Rice
Frances
F
Tunstall
Nigel
N
Jones
Sue
S
Moore
Pamela
P
Wavrant DeVrieze
Fabienne
F
Myers
Amanda
A
Crook
Richard
R
Compton
Danielle
D
Marshall
Helen
H
Meyer
David
D
Shears
Shantia
S
Booth
Jeremy
J
Ramic
Dzanan
D
Williams
Nigel
N
Norton
Nadine
N
Abraham
Richard
R
Kehoe
Pat
P
Williams
Hywel
H
Rudrasingham
Varuni
V
O'Donovan
Mick
M
Jones
Lesley
L
Hardy
John
J
Goate
Alison
A
Lovestone
Simon
S
Owen
Michael
M
Williams
Julie
J
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
D001057:Apolipoproteins E