Year: 2010
Type: article
Study design: Observational Study
Abstract: Most interstitial brain Aß appears to be linked to synaptic activity and endocytosis. Since proteins in the SNARE complex are essential for vesicle-mediated synaptic transmission, we queried the lympblastoid cell line (LCLs) expression database created by Dixon et al. for expression SNPs (eSNPs) in genes encoding SNARE proteins. This search identified multiple eSNPs in VAMP1, which encodes vesicle associated membrane protein 1, that were unequivocally associated with the level of VAMP1 transcript in LCLs (1.5 x 10 > p < 7.3 x 10). Among the eSNPs identified using LCLs, three (rs2532501, rs1048402 and rs7134136) were genotyped and showed suggestive association in our genome-wide association study (844 cases, 1255 controls) of late-onset Alzheimer's disease (LOAD). To pursue these findings, we searched VAMP1 and identified five known SNPs in putative functional regions (>70% conservation mouse vs. human). Among these was rs12964 (which had a p value of 3.3 x 10 in LCLs) and rs7390 (a good proxy for three of the LCL eSNPs: rs2532501, rs1048402, and rs7134136). VAMP1 SNPs were tested for association with late onset Alzheimer's disease (LOAD) using an expanded Mayo case-control series (1700 cases, 2300 controls). We also tested for association with the level of VAMP1 transcript in brain by measuring VAMP1 expression in 374 frozen cerebellar samples obtained at autopsy (Taqman low density arrays, Applied Biosystem). In cerebellar samples, as in LCLs, SNPs rs2532501, rs1048402, and rs7134136 were unequivocally associated with an increased level of VAMP1 transcript (1.95 x 10 > p < 1.31 x 10). Rs12964 was unequivocally associated with a decreased level of VAMP1 transcript (p = 6.55 x 10). Rs12964 was also associated with decreased risk of LOAD (p = 0.039), and rs7390 (proxy for rs2532501, rs1048402, and rs7134136) was associated with increased risk of LOAD (p = 0.041). VAMP1 SNPs unequivocally associated with increased expression are associated with increased risk of LOAD; VAMP1 SNPs unequivocally associated with decreased expression are associated with decreased risk of LOAD. These results suggest that VAMP1 may be a novel LOAD gene with eSNPs that influence risk of LOAD by altering vesicle mediated synaptic transmission.
Source: Alzheimer s & Dementia
Institutions: Mayo Clinic, Mayo Clinic in Florida
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1983069702