Article

Results of a high-resolution genome screen of 437 Alzheimer's disease families.

Massachusetts General Hospital, Charlestown, MA, USA.
Human Molecular Genetics (impact factor: 7.64). 01/2003; 12(1):23-32. pp.23-32
Source: PubMed

ABSTRACT Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

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Keywords

'highly significant' linkage peak
 
21q22-met criteria
 
9 cM genome screen
 
additional susceptibility genes
 
Alzheimer's disease
 
complex inheritance
 
devastating neurodegenerative disorder
 
epsilon 4
 
false positives
 
full National Institute
 
gene encoding apolipoprotein E
 
Kruglyak criteria
 
last decade
 
late-onset AD
 
multipoint lod score
 
non-parametric linkage analyses
 
Performing standard parametric
 
recent study
 
typical late-onset
 
valuable framework