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

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.

Two Novel PDE11A Genetic Variants Increase Tau Phosphorylations in Early-onset Alzheimer's Disease

“…High-penetrant mutations in amyloid precursor protein (APP) and the presenilins 1 and 2 (PSEN1 and PSEN2) are the main genetic risk factors underlying EOAD but are only found in approximately 11% of all EOAD patients [6]. Whole-exome sequencing (WES) has recently identi ed rare missense variants in TREM2, ABCA7, CASP7, ADAM10 and other genes that increase the risk for developing AD [7][8][9][10][11]. However, a large number of EOAD patients remain genetically unexplained.…”

Evaluating the contribution of cell-type specific alternative splicing to variation in lipid levels

“…The sQTL is hypothesized to be the causal signal, as it is associated with the production of a nonfunctional transcript. 11,12 Functional studies of eQTLs have been hindered by the time and energy required to identify and then mechanistically characterize the QTLs in model systems. QTL discovery efforts in primary tissues have been highly productive, but have several important drawbacks, such as the reliance on heterogeneous post-mortem tissue collection and the difficulty of interrogating phenotypes in tissues.…”

Novel Alzheimer’s disease risk genes: exhaustive investigation is paramount

“…The review cluster in this issue of Acta Neuropathologica provides detailed discussions of three of these AD risk genes (SORL1, CD33 and ABCA7) for which significant advances have been made in identifying genetic variants that directly modulate Alzheimer's disease risk [3][4][5]. A fourth paper gives a bird's-eye view of the new genetic landscape of AD, and uses recent experimental evidence on AD genes to give a different interpretation of the GWAS data in the shape of a new model of AD pathogenesis [6].…”

“…Several important messages can be gathered from these reviews. Both SORL1 and ABCA7, which were reported as Alzheimer's disease risk genes based on the association of common variants, were subsequently shown to harbor numerous rare deleterious variants which were detected more often in AD patients than in cognitively healthy individuals [3,5]. While logical in hindsight, these were important breakthroughs stirring the prevailing notion that the genetic architecture of complex AD was dominated by APOE ɛ4 and common variants with small effects.…”

“…The protective role of the sorLA protein in AD had already been studied extensively, but the functionality of some of its protein domains was still incompletely understood [3]. The effect ABCA7 may exert on AD risk is still uncertain [5]. The rare predicted loss-of-function variants in ABCA7 and SORL1 can now guide the design of experimental investigation of their molecular effect in the context of AD.…”