Recent genome-wide association studies have identified 78 loci associated with Parkinson's Disease susceptibility but the underlying mechanisms remain largely unclear. To identify variants likely causal for disease risk, we fine-mapped these Parkinson's-associated loci using four different statistical and functional fine-mapping methods. We then integrated multi-assay cell-type-specific epigenomic profiles to pinpoint the likely mechanism of action of each variant, allowing us to identify Consensus SNPs that disrupt LRRK2 and FCGR2A regulatory elements in microglia, MBNL2 enhancers in oligodendrocytes, and DYRK1A enhancers in neurons. Finally, we confirmed the functional relevance of fine-mapped SNPs using a suite of in silico validation approaches. Together, these results provide a robust list of likely causal variants underlying Parkinson's Disease risk for further mechanistic studies.

中文翻译：

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帕金森氏病易感基因座的精细映射可确定推定的因果变异

最近的全基因组关联研究已经确定了与帕金森氏病易感性相关的78个基因座，但基本机制仍不清楚。为了确定可能导致疾病风险的变异，我们使用四种不同的统计和功能精细映射方法精细映射了这些与帕金森氏症相关的基因座。然后，我们整合了多种测定细胞类型的特定表观基因组概况，以查明每种变体的可能作用机制，从而使我们能够识别破坏小胶质细胞中LRRK2和FCGR2A调控元件的共识SNP，少突胶质细胞中MBNL2增强剂和神经元中DYRK1A增强剂。最后，我们使用一套计算机验证方法确认了精细映射的SNP的功能相关性。一起，