Expression QTL Studies in LOAD and PSP Brains by Next-Generation RNA Sequencing (P2.147)

OBJECTIVE: To identify novel functional genetic variants that influence disease risk and brain gene expression in late-onset Alzheimer’s disease (LOAD) and progressive supranuclear palsy (PSP) by “Next-generation RNA-sequencing (RNA-seq)”. BACKGROUND: We previously determined by microarray expression studies that variants at LOAD and PSP GWAS loci associate with brain expression levels of nearby genes. Next-generation RNA-seq can provide detailed information on transcriptional changes at a greater dynamic range than microarray approach. We performed RNA-seq in the temporal cortex tissue of ~100 LOAD and ~100 PSP subjects. Our first aim is to assess the LOAD and PSP GWAS risk loci for association with RNA-seq gene and exon levels. Our second aim is to assess the influence on transcriptional regulation of all variants that are detected by RNA-seq. DESIGN/METHODS: Library preparations and RNA-seq as paired-end 51 base pair runs on Illumina HiSeq2000 were carried out at the Mayo Clinic Advanced Genomic Technology Center (AGTC). Data analysis including read alignments, tabulation of detected genes and exons and their levels was completed utilizing the infrastructure and analytic pipelines established at the Mayo Bioinformatics Core (BIC). Gene expression levels were tested for association with cis variants (+/- 1Mb) and all tests were adjusted for relevant biological and technical covariates. RESULTS: For cis -eQTL analysis, 4,799,008 gene-SNP pairs were considered. False discovery rates (FDRs) were calculated according to Benjamini and Hochberg procedure to account for multiple hypothesis-testing correction. 1751 and 700 cis -eQTLs were detected at FDR cis -eQTLs. At FDR cis -eQTLs were detected with 541 common results. CONCLUSIONS: The cis -eQTLs identified in this RNA-seq data will be utilized to dissect the previously reported microarray expression associations and to identify novel cis-eQTL that also confer LOAD and PSP risk. Study Supported by: R01 AG032990, P50 AG016574, CurePSP Foundation, Mayo GHR Grant. Disclosure: Dr. Taner has nothing to disclose. Dr. Wang has nothing to disclose. Dr. Carrasquillo has nothing to disclose. Dr. Allen has nothing to disclose. Dr. Younkin has nothing to disclose. Dr. Serie has nothing to disclose. Dr. Pankratz has received research support from Abbott Laboratories, Inc. 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. 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. Asmann has nothing to disclose.