Accumulating evidence demonstrated that GABAergic dysfunction contributes to the pathogenesis of Alzheimer’s disease (AD). The GABA aminotransferase (ABAT) gene encodes a mitochondrial GABA transaminase and plays key roles in the biogenesis and metabolism of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter. In this study, we performed an integrative study at the genetic and expression levels to investigate the potential genetic association between the ABAT gene and AD. Through re-analyzing data from the currently largest meta-analysis of AD genome-wide association study (GWAS), we identified genetic variants in the 3’-UTR of ABAT as the top AD-associated SNPs (P < 1 × 10⁻⁴) in this gene. Functional annotation of these AD-associated SNPs indicated that these SNPs are located in the regulatory regions of transcription factors or/and microRNAs. Expression quantitative trait loci (eQTL) analysis and luciferase reporter assay showed that the AD risk alleles of these SNPs were associated with a reduced expression level of ABAT. Further analysis of mRNA expression data and single-cell transcriptome data of AD patients showed that ABAT reduction in the neuron is an early event during AD development. Overall, our results indicated that ABAT genetic variants may be associated with AD through affecting its mRNA expression. An abnormal level of ABAT will lead to a disturbance of the GABAergic signal pathway in AD brains.

越来越多的证据表明 GABAergic 功能障碍有助于阿尔茨海默病 (AD) 的发病机制。的GABA转氨酶（ABAT）基因编码线粒体GABA转氨酶和γ-氨基丁酸的生物合成和代谢（GABA），这是一个主要的抑制性神经递质起着关键的作用。在这项研究中，我们在遗传和表达水平上进行了综合研究，以研究ABAT基因与 AD之间的潜在遗传关联。通过重新分析当前最大的 AD 全基因组关联研究 (GWAS) 荟萃分析的数据，我们将ABAT 3'-UTR 中的遗传变异确定为与 AD 相关的最高 SNP（P  < 1 × 10⁻⁴ ) 在这个基因中。这些与 AD 相关的 SNP 的功能注释表明这些 SNP 位于转录因子或/和 microRNA 的调控区域。表达数量性状基因座 (eQTL) 分析和荧光素酶报告基因分析表明，这些 SNP 的 AD 风险等位基因与ABAT表达水平降低有关。对 AD 患者的 mRNA 表达数据和单细胞转录组数据的进一步分析表明，神经元中的ABAT减少是 AD 发展过程中的早期事件。总体而言，我们的结果表明ABAT遗传变异可能通过影响其 mRNA 表达与 AD 相关。ABAT异常水平 会导致 AD 大脑中 GABA 能信号通路的紊乱。