Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, University of Antwerp, CDE, Universiteitsplein 1, 2610, Antwerp, Belgium.
Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
Acta Neuropathol. 2019 Aug;138(2):201-220. doi: 10.1007/s00401-019-01994-1. Epub 2019 Mar 22.
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.
全基因组关联研究（GWAS）最初确定 ATP 结合盒，亚家族 A，成员 7（ABCA7）为阿尔茨海默病（AD）的新风险基因。从那时起，来自体外、体内和基于人类的研究的越来越多的证据证实并扩展了这种关联，使 ABCA7 成为早发性和晚发性 AD 最重要的风险基因之一，同时具有对 AD 风险具有相对较大影响的常见和罕见风险变体。在这篇综述中，我们对有关 ABCA7 的文献进行了全面评估，重点是与 AD 相关的人类组学研究（例如基因组学、转录组学和甲基组学）。在欧洲和非裔美国人人群中，ABCA7 可变数串联重复（VNTR）的扩展和常见的提前终止密码子（PTC）变体分别解释了间接的 ABCA7 GWAS 关联。罕见的 ABCA7 PTC 变体在 AD 患者中强烈富集，其中一些具有类似于常染色体显性 AD 的遗传模式。此外，AD 患者中罕见的错义变体比健康对照更频繁，而常见的 ABCA7 错义变体可能对疾病具有保护作用。ABCA7 基因座的几个 CpG 位点的甲基化与 AD 显著相关。此外，ABCA7 包含许多不同的异构体，并且已经显示 ABCA7 剪接与 AD 相关。除了与疾病状态的关联外，这些遗传和表观遗传 ABCA7 标志物还与 AD 内表型显示出显著相关性；特别是淀粉样蛋白沉积和大脑形态。总之，基于人类的组学研究提供了（部分）ABCA7 缺失作为 AD 病理机制的证据，未来的研究应该明确干预 ABCA7 表达是否可以作为 AD 的有价值的治疗靶点。
