An <i>ABCA1</i> missense variant decreases cholesterol efflux and confers Alzheimer's disease risk in the Chinese population

BackgroundGenetic studies have revealed that single-nucleotide polymorphisms (SNPs) of <i>ABCA1</i> are associated with Alzheimer's disease (AD) risk. However, their AD-related effects in non-European populations are not well studied. Moreover, the functional implications of these AD-associated SNPs remain unclear.ObjectiveWe examined the AD associations of <i>ABCA1</i> SNPs in the Chinese population and investigated the underlying mechanisms whereby these SNPs modulate AD risk.MethodsWe conducted a genetic analysis in a Hong Kong Chinese AD cohort (<i>n</i> = 332 patients with AD, <i>n</i> = 316 normal controls). Specifically, we analyzed 6 independent <i>ABCA1</i> SNPs reported to be associated with AD risk in populations of European descent. To investigate the effects of these SNPs on ABCA1 protein function and brain molecular phenotypes, we analyzed cholesterol efflux in human glioblastoma cells as well as the associations between the AD risk SNPs and brain transcriptomic profiles, respectively.ResultsThe <i>ABCA1</i> coding SNP, rs2230806 (p.R219 K), was significantly associated with AD in the Chinese population, specifically in females (odds ratio [95% confidence interval] = 1.65 [1.16-2.33]). Notably, human glioblastoma cells expressing the <i>ABCA1</i> R219 K showed a 17% cholesterol efflux reduction (<i>p</i> < 0.001). Moreover, <i>ABCA1</i> rs2230806 was associated with changes in the expression of oligodendrocyte genes involved in myelination in the brain in females.ConclusionsWe identified a significant AD risk <i>ABCA1</i> coding variant in the Chinese population and demonstrated its effects on cholesterol efflux and brain molecular phenotypes. These results shed light on the genetic basis whereby an <i>ABCA1</i> genetic variant contributes to AD pathogenesis.