In the past, the field of Alzheimer disease (AD) genetics has benefited from the development of innovative paradigms that incorporate the latest genomic technologies combined with pristine patient data to dissect its complex etiology. Our group has successfully used this paradigm in both the identification of the APOE risk effect and more recently the glutathione S-transferase Omega-1 (GSTO1) age at onset (AAO) effect in AD. There is a new appreciation of the power of incorporating clinical phenotypes and developing clinical subphenotypes in attacking complex disorders. In addition, molecular genetic methods have continued to advance rapidly. Whole genome association (WGA) is a new approach that allows the direct evaluation of 300,000- 1,000,000 SNPs from across the genome for association with AD and provides the opportunity to perform a much more detailed examination of the genome than linkage studies. However, while the information content of WGA is extraordinarily high, the initial false positive rate using standard analyses is also high. Investigating each of the thousands of markers that will reach nominal significance is an ominous and inefficient task. One solution to this problem is the genomic convergence approach, which integrates disparate data types to sift through the volumes of existing data to prioritize the best candidate genes for intensive analysis. We have already demonstrated the utility of this approach with the identification of the GSTO1 gene. Thus we are proposing a WGA study of AD and will filter the results using existing linkage, candidate gene, and our recently generated microarray and Serial Analysis of Gene Expression (SAGE) data. A small set of candidate genes identified in multiple of these studies will be the focus of intensive follow-up analysis. Of particular importance will be our ability to follow-up using detailed clinical data on movement and psychiatric symptoms in a newly collected case-control dataset. Our unique position will enable us to marry the most powerful of new genomic approaches, WGA, to existing information to elucidate additional genetic effects contributing to this important neurodegenerative disease. The knowledge derived from this study will further our understanding of AD and will be crucial for future studies to develop and evaluate interventions. The knowledge derived from this study will further our understanding of the genetic etiology of AD. This understanding will be crucial for future studies to develop early interventions and more focused treatments, which will help alleviate the suffering of those with the disease and their families. ? ? ? ?
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