There are many active research projects accessing and applying shared ADNI data. Use the search above to find specific research focuses on the active ADNI investigations. This information is requested annually as a requirement for data access.
| Principal Investigator | |
| Principal Investigator's Name: | Chang-En Yu |
| Institution: | VA Puget Sound Health Care System |
| Department: | Geriatric Research Education and Clinical Center |
| Country: | |
| Proposed Analysis: | Title: Analysis of TOMM40 gene promoter haplotype in Alzheimer’s disease Background and Significance: The APOE locus is strongly associated with the risk of Alzheimer’s disease (AD). This locus consists of three genes (i.e., TOMM40, APOE, and APOC1) that are in tight linkage disequilibrium with each other, and their independent effect in AD cannot be easily separated. Although APOE ε4 allele is associated with an increased risk of AD but ε4-carriers do not always developed AD, suggesting that variants of ε4-linked haplotype in the APOE locus may express diverse risk effects for AD. We have applied a molecular haplotyping approach to study TOMM40 haplotypes that are linked to either ε3 or ε4 of the APOE. These haplotypes were constructed from a small number of human subjects (n = 40), which are the DNA collections of the Alzheimer’s Disease Research Center at University of Washington. Our data show that a single major TOMM40 promoter haplotype (> 93% in tested subjects) is linked with ε3, while three haplotype variants are linked with ε4 with frequency ranging from 14% to 63% in tested subjects. Thus, we hypothesize that variants of the ε4-linked TOMM40 promoter haplotypes are associated with different risk for AD. Because TOMM40 promoter will influence Tom40 protein production and mitochondrial function, such attribute is likely to have a direct impact on AD risk. Ideally, this hypothesis should be tested in the ε4/ε4 homozygous subjects; however, due to the limited sample size for ε4/ε4 homozygous subjects without AD, such analysis may not be feasible. Alternatively, because there is only one single major ε3-linked haplotype that is distinct from the three ε4-linked haplotypes, we will be able to examine effect of ε4-linked haplotypes variants in the subjects with APOE ε3/ε4 with greater statistical power. In this proposal, we plan to extend our study to a larger sample, and the ADGC data is ideal for such study. Research Design and Analysis: We will use the existing ADGC SNP data to re-construct promoter haplotype of the TOMM40. We will select subjects that are either homozygous (i.e., ε4/ε4) or heterozygous (i.e., ε3/ε4) with APOE genotype and extract their SNPs data around the promoter region of TOMM40. The single major ε3-linked haplotype will be designated as haplotype A. The primary interest in this proposed study is to determine which variants of ε4-linked haplotypes (designated haplotype B, C, and D) is associated with a lower risk of AD. For the subjects with APOE genotype ε4/ε4, we will estimate relative risk associated with each specific haplotype B, C, and D using logistic regression analysis. Haplotype B will be defined as reference group. For the subjects with APOE genotype ε3/ε4, there will be 6 potential diplotypes. Again, logistic regression analysis will be used to determine which ε4-linked haplotype is associated with a lower risk of AD. Genotype of A/B will be used as a reference group in this analysis. Age, sex and ethnicity will be adjusted in both analyses. Finally, we will examine the associations of each genotype with age at onset and pathological features of AD (Braak Stage and CERAD score). |
| Additional Investigators | |
| Investigator's Name: | Jessica Tulloch |
| Proposed Analysis: | See Analysis for Chang-En Yu. |
