Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia.
Griffith Institute for Drug Discovery (GRIDD), Griffith University, Brisbane, Australia.
Nat Commun. 2020 Mar 6;11(1):1238. doi: 10.1038/s41467-020-15065-7.
An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.
由于随着人口老龄化，受影响个体的数量预计将迅速增加，因此迫切需要深入了解帕金森病（PD）的病因机制。我们展示了一项基于血液的 PD 全基因组甲基化关联研究的结果，该研究涉及来自两个独立队列的 1132 例病例和 999 例对照的 229K CpG 探针的荟萃分析。我们确定了两个与 PD 相关的先前未报道的全基因组显著关联，包括 4 号染色体上的 cg06690548。我们证明 PD 中的 cg06690548 高甲基化与 SLC7A11 基因的下调有关，并且表明这与环境暴露一致，而不是与 DNA 甲基化或基因表达有关的药物或遗传因素。这些发现值得注意，因为 SLC7A11 编码一种调节抗氧化剂谷胱甘肽水平的半胱氨酸-谷氨酸反式载体，并且它是环境神经毒素 β-甲基氨基-L-丙氨酸（BMAA）的已知靶标。我们的研究确定 SLC7A11 基因为 PD 中的一个合理的生物学靶标。
