Genetic complexity in the BIN1 locus

Genetic complexity in the BIN1 locus Background Genome-wide association studies (GWAS) have identified a region upstream of bridging integrator 1 (BIN1 or AMPHIPHYSIN II) as the most important genetic susceptibility locus in Alzheimer's disease (AD) after Apolipoprotein E. To identify potential functional variants that were able to explain the association of BIN1 with AD, we undertook imputation of 556 genotypes in our French EADI1 cohort using the 1000 Genomes data set. In addition to the originally associated single nucleotide polymorphism (SNP) rs744373, we observed 13 imputed SNPs in the BIN1 region associated with AD risk. Here, we investigated if these 14 SNPs affected transcriptional activity in vitro using luciferase reporter assays. Methods Luciferase assay: HEK293 and SKNSH-SY5Y cell lines were transfected with pGL3promoter plasmids containing a sequence of 60 bp encompassing the polymorphisms of interest (wild-type or mutant).mRNA quantification : mRNAs were extracted from frontal brain tissues of 64 controls and 64 AD cases. The BIN1 transcripts were quantified by the Quantigene® technology (Panomics). Genetic analysis: In addition to SNPs, Insertion/deletion variations (Indels) were imputed using Impute2 and genotyped by direct sequencing in our different samples. Results We observed that n one of these 14 SNPs modified transcriptional activity. However, LD block analysis indicated Alzheimer's and Dementia Elsevier

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