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ABCA7 expression is associated with Alzheimer's disease polymorphism and disease status.

ABSTRACT: Genome-wide association studies (GWAS) have implicated a series of single nucleotide polymorphisms (SNPs) in Alzheimer's disease (AD) risk. Elucidating the function of these SNPs is critical to identify the underlying pathways and, potentially, novel therapeutic agents. SNPs within the gene ATP binding cassette A7 (ABCA7) reached significance in these studies, warranting investigation into their actions. Here, we analyzed ABCA7 expression in a set of human brain samples as a function of AD-associated SNPs and AD status. We report that the rs3764650T allele that decreases AD risk is associated with increased ABCA7 expression. However, ABCA7 expression is increased in AD individuals. We interpret our findings as suggesting a model wherein increased ABCA7 expression reduces AD risk and that the increased ABCA7 observed in AD reflects an inadequate compensatory change.

SUBMITTER: Vasquez JB

PROVIDER: S-EPMC3863933 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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ABCA7 expression is associated with Alzheimer's disease polymorphism and disease status.

Vasquez Jared B JB Fardo David W DW Estus Steven S

Neuroscience letters 20131018

Genome-wide association studies (GWAS) have implicated a series of single nucleotide polymorphisms (SNPs) in Alzheimer's disease (AD) risk. Elucidating the function of these SNPs is critical to identify the underlying pathways and, potentially, novel therapeutic agents. SNPs within the gene ATP binding cassette A7 (ABCA7) reached significance in these studies, warranting investigation into their actions. Here, we analyzed ABCA7 expression in a set of human brain samples as a function of AD-assoc ...[more]

PMID: 24141082

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Project description:Premature termination codon (PTC) mutations in the ATP-Binding Cassette, Sub-Family A, Member 7 gene (ABCA7) have recently been identified as intermediate-to-high penetrant risk factor for late-onset Alzheimer's disease (LOAD). High variability, however, is observed in downstream ABCA7 mRNA and protein expression, disease penetrance, and onset age, indicative of unknown modifying factors. Here, we investigated the prevalence and disease penetrance of ABCA7 PTC mutations in a large early onset AD (EOAD)-control cohort, and examined the effect on transcript level with comprehensive third-generation long-read sequencing. We characterized the ABCA7 coding sequence with next-generation sequencing in 928 EOAD patients and 980 matched control individuals. With MetaSKAT rare variant association analysis, we observed a fivefold enrichment (p = 0.0004) of PTC mutations in EOAD patients (3%) versus controls (0.6%). Ten novel PTC mutations were only observed in patients, and PTC mutation carriers in general had an increased familial AD load. In addition, we observed nominal risk reducing trends for three common coding variants. Seven PTC mutations were further analyzed using targeted long-read cDNA sequencing on an Oxford Nanopore MinION platform. PTC-containing transcripts for each investigated PTC mutation were observed at varying proportion (5-41% of the total read count), implying incomplete nonsense-mediated mRNA decay (NMD). Furthermore, we distinguished and phased several previously unknown alternative splicing events (up to 30% of transcripts). In conjunction with PTC mutations, several of these novel ABCA7 isoforms have the potential to rescue deleterious PTC effects. In conclusion, ABCA7 PTC mutations play a substantial role in EOAD, warranting genetic screening of ABCA7 in genetically unexplained patients. Long-read cDNA sequencing revealed both varying degrees of NMD and transcript-modifying events, which may influence ABCA7 dosage, disease severity, and may create opportunities for therapeutic interventions in AD.

Dataset Information

ABCA7 expression is associated with Alzheimer's disease polymorphism and disease status.

Publications

ABCA7 expression is associated with Alzheimer's disease polymorphism and disease status.

Similar Datasets

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