Parkinson’s disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD and to identify novel mechanisms conferring risk for the disease, we fine-mapped the 17q21.31 locus by constructing discrete haplotype blocks from genetic data. We used digital PCR to assess copy number variation associated with PD-associated blocks, and used human brain postmortem RNA-seq data to identify candidate genes that were then further investigated using in vitro models and human brain tissue. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble α-synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with α-synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

中文翻译：

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H1 相关帕金森病风险的 17q21.31 亚单倍型与星形胶质细胞中 LRRC37A/2 表达相关

帕金森病 (PD) 在遗传上与 MAPT 17q.21.31 基因座的 H1 单倍型相关，但这种关联背后的致病基因和变异尚未确定。为了更好地了解该区域对 PD 的遗传贡献并确定导致该疾病风险的新机制，我们通过从遗传数据构建离散单倍型块来精细绘制 17q21.31 基因座。我们使用数字 PCR 来评估与 PD 相关块相关的拷贝数变异，并使用人脑死后 RNA-seq 数据来识别候选基因，然后使用体外模型和人脑组织进一步研究这些候选基因。我们在与 PD 风险相关的 17q21.31 位点上发现了三个新的 H1 亚单倍型块。保护性亚单倍型与人脑组织中 LRRC37A/2 拷贝数和表达的增加相关。我们发现 LRRC37A/2 是一种膜相关蛋白，在细胞迁移、趋化性和星形胶质细胞炎症中发挥作用。在人黑质中，LRRC37A/2 主要在星形胶质细胞中表达，与可溶性 α-突触核蛋白直接相互作用，并与 PD 脑组织中的路易体共定位。这些数据表明，一个新的候选基因 LRRC37A/2 通过与 α-突触核蛋白的相互作用及其对星形胶质细胞功能和炎症反应的影响，有助于 17q21.31 位点与 PD 之间的关联。这些数据首次将 17q21.31 位点的遗传关联与 PD 病理联系起来，并强调了 17q21.31 位点的变异在调节 MAPT 和 KANSL1 以外的多个基因中的重要性，及其与 PD 病理学的相关性。非神经元细胞类型。