Functional variants in AKAP9, ABCA7 and previously identified AD-associated
genes that contribute directly to AD risk in African Americans
 
   Lead Investigator:    Lindsay Farrer
   Institution      :    Boston ADC
   E-Mail           :    farrer@bu.edu
   Proposal ID      :    571



   Proposal Description:
   We propose to use extensive clinical and genetic resources assembled by us and the AD Genetics Consortium to identify functional variants in AKAP9, ABCA7 and previously identified AD associated genes that contribute directly to AD risk in African Americans (AAs). To accomplish this goal we will resequence the coding and regulatory regions of these genes in 500 AA AD probands and 500 AA age-matched cognitively normal controls. Data will be evaluated using  bioinformatic tools to identify functional variants that may directly influence AD pathogenesis. Potentially important functional variants will be tested for association in the discovery AA cohort and a replication AA cohort containing 1000 cases and 2000 controls. We will attempt to generalize these findings in EAs by evaluating top-ranked variants using publically available data to determine if variants identified in AAs are also important in EAs. Gene expression and RNA-Seq experiments will be performed in brain tissue from AA and EA cases and controls to identify variants that may regulate transcription of alternative isoforms. The most promising variants in ABCA7 and AKAP9 will be introduced into neuronal cells to evaluate their effects on expression and processing of APP, tau and other important AD markers. Finally, we will confirm the importance of these genes by demonstrating altered expression in neuropathologically confirmed brain specimens from AD cases and controls.