Department of Neurology, Oslo University Hospital, Oslo, Norway.
Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Ann Neurol. 2021 May;89(5):942-951. doi: 10.1002/ana.26032. Epub 2021 Mar 4.
Understanding how different parts of the immune system contribute to pathogenesis in Parkinson's disease is a burning challenge with important therapeutic implications. We studied enrichment of common variant heritability for Parkinson's disease stratified by immune and brain cell types.
We used summary statistics from the most recent meta-analysis of genomewide association studies in Parkinson's disease and partitioned heritability using linkage disequilibrium score regression, stratified for specific cell types, as defined by open chromatin regions. We also validated enrichment results using a polygenic risk score approach and intersected disease-associated variants with epigenetic data and expression quantitative loci to nominate and explore a putative microglial locus.
We found significant enrichment of Parkinson's disease risk heritability in open chromatin regions of microglia and monocytes. Genomic annotations overlapped substantially between these 2 cell types, and only the enrichment signal for microglia remained significant in a joint model. We present evidence suggesting P2RY12, a key microglial gene and target for the antithrombotic agent clopidogrel, as the likely driver of a significant Parkinson's disease association signal on chromosome 3.
Our results provide further support for the importance of immune mechanisms in Parkinson's disease pathogenesis, highlight microglial dysregulation as a contributing etiological factor, and nominate a targetable microglial gene candidate as a pathogenic player. Immune processes can be modulated by therapy, with potentially important clinical implications for future treatment in Parkinson's disease. ANN NEUROL 2021;89:942-951.
了解免疫系统的不同部分如何导致帕金森病的发病机制，是一个具有重要治疗意义的热点挑战。我们研究了根据免疫和脑细胞类型分层的帕金森病常见变异遗传率的富集情况。
我们使用了帕金森病全基因组关联研究最近荟萃分析的汇总统计数据，并使用连锁不平衡评分回归根据开放染色质区域定义的特定细胞类型进行遗传率分层。我们还使用多基因风险评分方法验证了富集结果，并将疾病相关变体与表观遗传数据和表达数量性状基因座进行交叉，以提名和探索一个可能的小胶质细胞基因座。
我们发现帕金森病风险遗传率在小胶质细胞和单核细胞的开放染色质区域中显著富集。这两种细胞类型的基因组注释有很大的重叠，只有小胶质细胞的富集信号在联合模型中仍然显著。我们提出的证据表明，P2RY12 是一种关键的小胶质细胞基因，也是抗血小板药物氯吡格雷的靶点，可能是 3 号染色体上显著帕金森病关联信号的驱动因素。
我们的研究结果进一步支持了免疫机制在帕金森病发病机制中的重要性，强调了小胶质细胞失调作为一个致病因素的作用，并提名了一个可靶向的小胶质细胞基因候选物作为一个致病因素。免疫过程可以通过治疗来调节，这对未来帕金森病的治疗具有潜在的重要临床意义。
