Alzheimer disease (AD) is a leading cause of dementia in the elderly. Identifying susceptibility genes for AD will aid in risk assessment, diagnosis and understanding the etiology of the disease. Several chromosomal regions have been identified as harboring genes for late-onset AD, but only one gene, APOE, has been demonstrated consistently to be directly involved in disease risk. While APOE may explain up to half of the genetic effect in late-onset AD, the remaining susceptibility genes have been difficult to identify. A large number of candidate genes have been tested for association using either case-control tests in unrelated individuals or family-based association tests, but the results have varied greatly between studies. It is our hypothesis that epistatic effects among multiple genes play a more important role in determining risk of AD than the independent effects of any single gene. The multiple positive and negative reports for numerous candidate gene association studies may in fact be due to study designs that only evaluate each candidate gene for main effects that are independent of all other genes. The goal of this proposal is to determine the role of epistasis or nonadditive gene-gene interactions on the risk of late-onset AD. To accomplish this goal, we propose to identify and genotype several single nucleotide polymorphisms in ten AD candidate genes for which there have been conflicting association studies. We will use a family-based design using affected and unaffected siblings and propose to study 800 sibships containing approximately 1600 individuals. We will extend the recently developed pedigree disequilibrium test (PDT) to test for associations at the genotypic level and allow its incorporation into the new multifactor dimensionality reduction (MDR) method. To test for complex genetic interactions in these data, we will use this modified MDR-PDT method. We anticipate that these results will explain at least some of the inconsistency arising from Alzheimer disease candidate gene association studies. Further, knowledge gained from the proposed research will be invaluable for public health efforts to prevent and treat the initiation, progression, and severity of Alzheimer disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020135-03
Application #
6728253
Study Section
Special Emphasis Panel (ZRG1-SNEM-3 (04))
Program Officer
Miller, Marilyn
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$505,425
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Naj, Adam C; Beecham, Gary W; Martin, Eden R et al. (2010) Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities. PLoS Genet 6:e1001130
Lambert, Jean-Charles; Sleegers, Kristel; González-Pérez, Antonio et al. (2010) The CALHM1 P86L polymorphism is a genetic modifier of age at onset in Alzheimer's disease: a meta-analysis study. J Alzheimers Dis 22:247-55
Beecham, Gary W; Naj, Adam C; Gilbert, John R et al. (2010) PCDH11X variation is not associated with late-onset Alzheimer disease susceptibility. Psychiatr Genet 20:321-4
Beecham, Gary W; Martin, Eden R; Gilbert, John R et al. (2010) APOE is not associated with Alzheimer disease: a cautionary tale of genotype imputation. Ann Hum Genet 74:189-94
Edwards, Todd L; Turner, Stephen D; Torstenson, Eric S et al. (2010) A general framework for formal tests of interaction after exhaustive search methods with applications to MDR and MDR-PDT. PLoS One 5:e9363
Bush, William S; Dudek, Scott M; Ritchie, Marylyn D (2009) Biofilter: a knowledge-integration system for the multi-locus analysis of genome-wide association studies. Pac Symp Biocomput :368-79
Liang, Xueying; Slifer, Michael; Martin, Eden R et al. (2009) Genomic convergence to identify candidate genes for Alzheimer disease on chromosome 10. Hum Mutat 30:463-71
Beecham, Gary W; Martin, Eden R; Li, Yi-Ju et al. (2009) Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease. Am J Hum Genet 84:35-43
Slifer, Michael A; Martin, Eden R; Gilbert, John R et al. (2009) Resolving the relationship between ApolipoproteinE and depression. Neurosci Lett 455:116-9

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