Studies of the genetic basis of Parkinson's disease (PD) have identified many disease-associated genetic variants, but the mechanisms linking variants to pathogenicity are largely unknown. PD risk is attributed to both coding mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene and to common non-coding variation upstream of the LRRK2 locus. Here we show that the influence of genotype at non-coding variant rs76904798 on LRRK2 expression is propagated specifically through microglia, in contrast to evaluations based on general rather than genotype-dependent expression. We find evidence of microglia-specific regulatory regions that may modulate LRRK2 expression using single nuclei sequencing analyses of human frontal cortex and confirm these results in a human induced pluripotent stem cell-derived microglia model. Our study demonstrates that cell type is an important consideration in interrogation of the role of non-coding variation in disease pathogenesis.

中文翻译：

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常见遗传变异与帕金森氏病的关系通过小胶质细胞传播

对帕金森氏病（PD）遗传基础的研究已经确定了许多与疾病相关的遗传变异，但将变异与致病性联系起来的机制尚不清楚。PD风险既归因于富含亮氨酸的重复激酶2（LRRK2）基因中的编码突变，也归因于LRRK2基因座上游的常见非编码变异。在这里，我们显示非编码变体rs76904798对LRRK2表达的基因型影响是通过小胶质细胞特异性传播的，这与基于一般而非基因型依赖性表达的评估相反。我们找到了小胶质细胞特异性调节区域的证据，该区域可能使用人类额叶皮层的单核测序分析来调节LRRK2表达，并在人诱导的多能干细胞衍生的小胶质细胞模型中证实了这些结果。