Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Henan Key Laboratory of Cerebrovascular Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
Mov Disord. 2023 Dec;38(12):2258-2268. doi: 10.1002/mds.29598. Epub 2023 Nov 21.
Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood.
The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci.
We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed.
MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes.
We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.
帕金森病（PD）患者的大脑结构一直存在异常，表明 PD 与大脑结构之间存在共同的病因和病理过程；然而，遗传关系仍不清楚。
本研究旨在探讨 PD 与脑结构表型（BSP）之间共享遗传结构的程度，并确定共享的基因组位点。
我们使用全基因组关联研究的汇总统计数据进行 MiXeR 分析和条件/联合假发现率（FDR）分析，以研究 PD 和 BSP 之间的共享遗传特征。随后还进行了人类大脑中的表达数量性状基因座（eQTL）映射和富集分析。
MiXeR 分析确定了 PD 与各种 BSP 之间存在遗传重叠，包括总皮质表面积、平均皮质厚度和特定的脑体积结构。使用条件 FDR 进行的进一步分析确定了 21 个新的 PD 风险位点与 BSP 相关，其条件 FDR < 0.01；联合 FDR 分析表明，PD 在联合 FDR < 0.05 的情况下与某些 BSP 共享几个基因组位点。在共享的位点中，16 个可信映射基因在大脑组织中表达水平较高，主要与免疫功能相关的生物学过程有关。
我们证实了 PD 和 BSP 之间存在混合方向等位基因效应的多基因重叠，并确定了多个共享的基因组位点和风险基因，这些基因可能与免疫相关的生物学过程有关。这些发现为 PD 相关的复杂遗传结构提供了新的见解。© 2023 国际帕金森病和运动障碍学会。
