Parkinson’s disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer’s Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted.

帕金森病 (PD) 是一种常见的神经退行性疾病，其风险比例很大，由遗传因素决定。尽管已经取得了很大进展，但大部分遗传性仍然未知。这部分是因为之前的遗传学研究主要集中在单核苷酸变异的贡献上。更复杂形式的变异，例如结构变异和串联重复，已经与几种突触核蛋白病相关。然而，由于通常需要更复杂的测序方法来检测这些区域，因此人们对它们对 PD 的贡献知之甚少。一个例子是SNCA基因内含子 4 中富含 CT 的多态性区域。该单倍型已被认为与阿尔茨海默病和SNCA基因表达中路易体 (LB) 病理学的风险相关，但尚未在 PD 中进行研究。在这里，我们尝试解析这种富含 CT 的单倍型并研究其在 PD 中的作用。我们对 1375 例 PD 病例和 959 例对照患者的该区域进行了靶向 PacBio HiFi 测序。我们复制了先前报道的关联以及两个 PD 风险 SNV（rs356182 和 rs5019538）与最大单倍型单倍型 4 之间的新关联。通过数量性状位点分析，我们确定了与替代 CAGE 转录起始位点使用相关的显着单倍型 4，但不会导致死后额叶皮层脑组织中SNCA基因表达的显着差异。因此，该位点的疾病关联可能不是由该富含 CT 的重复区域在生物学上驱动的。我们的数据证明了该SNCA区域的复杂性，并强调需要进一步的后续功能研究。