Booms Alix, Pierce Steven E, van der Schans Edwin J C, Coetzee Gerhard A
Center for Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI 49503, USA.
Van Andel Institute graduate student, Grand Rapids, MI 49503, USA.
iScience. 2024 Jan 17;27(2):108921. doi: 10.1016/j.isci.2024.108921. eCollection 2024 Feb 16.
Genome-wide association studies have identified thousands of single nucleotide polymorphisms that associate with increased risk for Parkinson's disease (PD), but the functions of most of them are unknown. Using assay for transposase-accessible chromatin (ATAC) and H3K27ac chromatin immunoprecipitation (ChIP) sequencing data, we identified 73 regulatory elements in microglia that overlap PD risk SNPs. To determine the target genes of a "risk enhancer" within intron two of , we used CRISPR-Cas9 to delete the open chromatin region where two PD risk SNPs reside. The loss of the enhancer led to reduced expression of multiple genes including and the adjacent gene . It also led to expression changes of genes involved in glucose metabolism, a process that is known to be altered in PD patients. Our work expands the role of in PD and provides a connection between PD-associated genetic variants and underlying biology that points to a risk mechanism in microglia.
全基因组关联研究已经鉴定出数千个与帕金森病（PD）风险增加相关的单核苷酸多态性，但其中大多数的功能尚不清楚。利用转座酶可及染色质分析（ATAC）和H3K27ac染色质免疫沉淀（ChIP）测序数据，我们在小胶质细胞中鉴定出73个与PD风险单核苷酸多态性重叠的调控元件。为了确定某基因内含子2中一个“风险增强子”的靶基因，我们使用CRISPR-Cas9删除了两个PD风险单核苷酸多态性所在的开放染色质区域。该增强子的缺失导致包括某基因及其相邻基因在内的多个基因表达降低。它还导致参与葡萄糖代谢的基因表达发生变化，而葡萄糖代谢过程在PD患者中已知会发生改变。我们的工作扩展了某基因在PD中的作用，并在PD相关遗传变异与潜在生物学之间建立了联系，这指向了小胶质细胞中的一种风险机制。
