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Acta neuropathologica
08, 2019;138 (2): 201-220.

The role of ABCA7 in Alzheimer's disease: evidence from genomics, transcriptomics and methylomics.

Arne De Roeck, Christine Van Broeckhoven, Kristel Sleegers
Author Information
  1. Arne De Roeck: Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp, CDE, Universiteitsplein 1, 2610, Antwerp, Belgium.
  2. Christine Van Broeckhoven: Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp, CDE, Universiteitsplein 1, 2610, Antwerp, Belgium.
  3. Kristel Sleegers: Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp, CDE, Universiteitsplein 1, 2610, Antwerp, Belgium. kristel.sleegers@uantwerpen.vib.be. ORCID
PMID: 30903345 DOI: 10.1007/s00401-019-01994-1

Abstract

Genome-wide association studies (GWAS) originally identified ATP-binding cassette, sub-family A, member 7 (ABCA7), as a novel risk gene of Alzheimer's disease (AD). Since then, accumulating evidence from in vitro, in vivo, and human-based studies has corroborated and extended this association, promoting ABCA7 as one of the most important risk genes of both early-onset and late-onset AD, harboring both common and rare risk variants with relatively large effect on AD risk. Within this review, we provide a comprehensive assessment of the literature on ABCA7, with a focus on AD-related human -omics studies (e.g. genomics, transcriptomics, and methylomics). In European and African American populations, indirect ABCA7 GWAS associations are explained by expansion of an ABCA7 variable number tandem repeat (VNTR), and a common premature termination codon (PTC) variant, respectively. Rare ABCA7 PTC variants are strongly enriched in AD patients, and some of these have displayed inheritance patterns resembling autosomal dominant AD. In addition, rare missense variants are more frequent in AD patients than healthy controls, whereas a common ABCA7 missense variant may protect from disease. Methylation at several CpG sites in the ABCA7 locus is significantly associated with AD. Furthermore, ABCA7 contains many different isoforms and ABCA7 splicing has been shown to associate with AD. Besides associations with disease status, these genetic and epigenetic ABCA7 markers also showed significant correlations with AD endophenotypes; in particular amyloid deposition and brain morphology. In conclusion, human-based -omics studies provide converging evidence of (partial) ABCA7 loss as an AD pathomechanism, and future studies should make clear if interventions on ABCA7 expression can serve as a valuable therapeutic target for AD.

Keywords

ATP-binding cassette, sub-family A, member 7 (ABCA7) Alzheimer’s disease Endophenotype Loss-of-function Meta-analysis Rare variants Variable number tandem repeat (VNTR)

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MeSH Term

ATP-Binding Cassette Transporters
Alzheimer Disease
Amyloid
Animals
Atrophy
Brain
Codon, Nonsense
Cognition
CpG Islands
DNA Methylation
Disease Models, Animal
Ethnicity
Female
Genes, Dominant
Genetic Predisposition to Disease
Genomics
Humans
Lipid Metabolism
Male
Mice
Minisatellite Repeats
Mutation, Missense
Polymorphism, Single Nucleotide
Risk
Transcriptome

Chemicals

ABCA7 protein, human
ATP-Binding Cassette Transporters
Abca7 protein, mouse
Amyloid
Codon, Nonsense
Journal Article Research Support, Non-U.S. Gov't Review
Article has an altmetric score of 45

Word Cloud

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