Investigation Of Transcriptional Regulation At The Alzheimer’s Disease Risk Loci. (S28.006)

OBJECTIVE:To investigate transcriptional regulation of late-onset Alzheimer’s disease (LOAD) GWAS risk loci genes in the human brain. BACKGROUND:We previously identified genetic associations of brain levels of genes at the LOAD risk GWAS loci ABCA7 , BIN1, CLU, CR1 and MS4A4A with cisSNPs, including some of the top AD risk variants. Recently, 11 additional risk loci were identified through a large meta-analysis of multiple LOAD GWAS. In this study, our first aim is to investigate the association of brain levels of these 11 novel LOAD risk loci genes with cis SNPs. Our second aim is to evaluate the potential role of alternative splicing in these gene expression associations. DESIGN/METHODS:We have already obtained gene expression measures of ~24,000 transcripts in two brain regions (temporal cortex and cerebellum) for ~ 200 AD subjects and ~200 subjects with other pathologies using Illumina’s WG-DASL assay. LOAD GWAS SNPs at the 11 novel loci will be analyzed for association with expression levels of the corresponding genes in cis , using linear regression adjusting for appropriate covariates. To evaluate alternative splicing, we will use NanoString nCounter™ technology to measure levels of all known transcripts of the candidate genes at all LOAD GWAS loci in ~350 brain RNA samples. RESULTS:We have previously demonstrated the utility of this approach and anticipate that there exist additional LOAD genes, brain levels of which are likewise influenced by SNPs. We postulate that some of these SNPs also confer LOAD risk and some of the expression associations are due to alternative splicing of exons. CONCLUSIONS:Many genes at the LOAD GWAS loci associate with cis SNPs, some of which are the top LOAD risk SNPs. This suggests that many LOAD GWAS variants confer risk by transcriptional regulation of genes at these loci. Dissection of this transcriptional regulation is expected to have implications in the understanding of LOAD pathophysiology. Study Supported by: R01 AG032990, P50 AG016574 Disclosure: Dr. Kachadoorian has nothing to disclose. Dr. Allen has nothing to disclose. Dr. Karhade has nothing to disclose. Dr. Karhade 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. Younkin has nothing to disclose. Dr. Dickson has received personal compensation for activities with Neotope, Inc. as a consultant. Dr. Taner has nothing to disclose.