Journal
HUMAN MOLECULAR GENETICS
Volume 12, Issue 1, Pages 23-32Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddg007
Keywords
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Funding
- NHGRI NIH HHS [N01-HG-65403] Funding Source: Medline
- NIMH NIH HHS [U01 MH46373, U01 MH46281, U01 MH46290] Funding Source: Medline
- NATIONAL HUMAN GENOME RESEARCH INSTITUTE [N01HG065403] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF MENTAL HEALTH [U01MH046281, U01MH046290, U01MH046373] Funding Source: NIH RePORTER
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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 (epsilon4) 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) greater than or equal to1.9 and/or multipoint lod score (MLS) greater than or equal to2.2] 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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