The Retinoic Acid Receptor Beta (Rarb) Region of Mmu14 Is Associated with Prion Disease Incubation Time in Mouse

Abstract

In neurodegenerative conditions such as Alzheimer's and prion disease it has been shown that host genetic background can have a significant effect on susceptibility. Indeed, human genome-wide association studies (GWAS) have implicated several candidate genes. Understanding such genetic susceptibility is relevant to risks of developing variant CJD (vCJD) in populations exposed to bovine spongiform encephalopathy (BSE) and understanding mechanisms of neurodegeneration. In mice, aspects of prion disease susceptibility can be modelled by examining the incubation period following experimental inoculation. Quantitative trait linkage studies have already identified multiple candidate genes; however, it is also possible to take an individual candidate gene approach. Rarb and Stmn2 were selected as candidates based on the known association with vCJD. Because of the increasing overlap described between prion and Alzheimer's diseases we also chose Clu, Picalm and Cr1, which were identified as part of Alzheimer's disease GWAS. Clusterin (Clu) was considered to be of particular interest as it has already been implicated in prion disease. Approximately 1,000 heterogeneous stock (HS) mice were inoculated intra-cerebrally with Chandler/RML prions and incubation times were recorded. Candidate genes were evaluated by sequencing the whole transcript including exon-intron boundaries and potential promoters in the parental lines of the HS mice. Representative SNPs were genotyped in the HS mice. No SNPs were identified in Cr1 and no statistical association with incubation time was seen for Clu (P=0.96) and Picalm (P=0.91). Significant associations were seen for both Stmn2 (P=0.04) and Rarb (P=0.0005), however, this was only highly significant for Rarb. This data provides significant further support for a role for the Rarb region of Mmu14 and Stmn2 in prion disease