Transcript Profiling Analysis Of Alzheimer’s Disease Brains. (I5-1.003)

OBJECTIVE: To use existing microarray data to identify genes that are differentially expressed in AD vs. non-AD brains. BACKGROUND: Despite the success of recent LOAD GWAS studies, much of the heritability of LOAD remains unexplained. We hypothesize that evaluation of brain gene expression provides an additional avenue for identification of novel LOAD genes and pathways that may be potential drug targets. We previously performed a gene expression GWAS that assessed mRNA levels of ~24,000 transcripts in two brain regions (temporal cortex and cerebellum) for ~ 200 AD subjects and ~200 subjects with other pathologies We have now performed transcript profiling analysis comparing gene expression levels between AD and non-AD subjects in both brain regions and conducted pathway analysis on these data. In addition, we are collecting whole genome CpG methylation data (methylome) on a subset of these subjects for future evaluation. DESIGN/METHODS: Gene expression levels were measured by the Illumina HT-12 V4 Expression BeadChip arrays using the Whole-Genome DASL HT assay and appropriate data quality control was implemented. Transcript profiling analysis was carried out in R using linear regression with appropriate covariates. Gene pathway analysis was executed using MetaCore for the two brain regions separately. RESULTS: Following QC ~17,000 gene expression measures were robustly detected in each brain region. Transcript profiling analysis identified 743 targets in the cerebellum and 2839 targets in the temporal cortex (un-corrected p-value <0.01) that were selected for pathway analysis. In the temporal cortex several significant pathways and GO Processes were identified including but not limited to oxidative phosphorylation and lipid metabolism. CONCLUSIONS: Transcript profiling and pathway analysis of brain gene expression data has identified several interesting targets for further exploration of molecular pathways involved in AD. The addition of methylome data will further enhance our understanding of the role of gene expression and control in this disease. Study Supported by: R01 AG032990, P50 AG016574, Mayo Clinic Center for Individualized Medicine Epigenomics Grant. Disclosure: Dr. Allen has nothing to disclose. Dr. Serie has nothing to disclose. Dr. Walsh has nothing to disclose. Dr. Zhifu has nothing to disclose. Dr. Baheti has nothing to disclose. Dr. Zou has nothing to disclose. Dr. Chai has nothing to disclose. Dr. Younkin has nothing to disclose. Dr. Crook has nothing to disclose. Dr. Pankratz has received research support from Abbott Laboratories, Inc. Dr. Carrasquillo has nothing to disclose. Dr. Nair has nothing to disclose. Dr. Middha has nothing to disclose. Dr. Maharjan has nothing to disclose. Dr. Nguyen has nothing to disclose. Dr. Ma has nothing to disclose. Dr. Malphrus has nothing to disclose. Dr. Lincoln has nothing to disclose. Dr. Bisceglio has nothing to disclose. Dr. Kolbert has nothing to disclose. Dr. Jen has nothing to disclose. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., and Janssen Alzheimer9s Immunotherapy. Dr. Petersen has received royalty payments from Oxford University Press. Dr. Graff-Radford has received personal compensation for activities with Codman as a member of a scientific advisory board. Dr. Graff-Radford has received personal compensation in an editorial capacity for The Neurologist. Dr. Graff-Radford has received research support from Janssen, Pfizer Inc., Medivation, Forest Laboratories Inc., and Allon. Dr. Dickson has received personal compensation for activities with Neotope, Inc. as a consultant. Dr. Younkin has nothing to disclose. Dr. Asmann has nothing to disclose. Dr. Taner has nothing to disclose.