研究帕金森病与黑质磁化率之间的共同遗传结构

Jilian Fu
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摘要

帕金森病(PD)是一种常见且逐渐恶化的神经退行性疾病,严重影响着全世界数百万人。神经影像学研究一致表明,黑质(SN)内的定量易感性图谱(QSM)异常与帕金森病有关。然而,帕金森病和黑质QSM之间的遗传基础仍然没有得到充分的了解。本研究利用PD (N = 501,348)和SN QSM (N = 35273)的最大全基因组关联研究的汇总统计数据,进行遗传多效性分析,以探索全局、局部和变异水平上的遗传重叠。我们观察到SN的PD与QSM在全球范围内具有显著的遗传相关性(rg = 0.096,与LDSC相比p = 0.032; rg = 0.097,与SumHer相比p = 0.048)。局部水平的分析确定了6个基因组区域,显示了与这两种特征的共同关联。在变异水平上,我们发现了SN的PD和QSM共有的12个遗传变异。这些共有的风险变异被映射到33个独特的基因上。我们分析了基于这些共享基因的药物-基因相互作用及其与PD药物的关联。这些发现阐明了SN磁化率与PD发病机制之间的遗传相互作用,揭示了潜在的生物标志物发现和治疗开发的靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Investigating the shared genetic architecture between Parkinson's disease and magnetic susceptibility of the substantia nigra

Investigating the shared genetic architecture between Parkinson's disease and magnetic susceptibility of the substantia nigra
Parkinson's disease (PD) is a common and progressively deteriorating neurodegenerative disorder thatprofoundly affects millions of individuals worldwide. Neuroimaging research has consistently demonstrated abnormalities in quantitative susceptibility mapping (QSM) within the substantia nigra (SN) that are associated with Parkinson's disease. However, the genetic underpinnings shared between Parkinson's disease and QSM of substantia nigra remain inadequately understood. Here, genetic pleiotropic analyses were conducted to explore genetic overlap at global, local, and variant levels byleveraging summary statistics from the largest genome-wide association studies for PD (N ​= ​501,348) and QSM of SN (N ​= ​35,273). We observed a significant global genetic correlation between PD and QSM of SN (rg ​= ​0.096, p ​= ​0.032 with LDSC; rg ​= ​0.097, p ​= ​0.048 with SumHer). Local-level analysis identified six genomic regions showing shared associations with the two traits. At the variant level, we found 12 genetic variants shared by PD and QSM of SN. These shared risk variants were mapped to 33 unique genes. We analyzed drug-gene interactions based on these shared genes and their associations with PD medications. These findings elucidate the genetic interplay between SN magnetic susceptibility and PD pathogenesis, revealing potential biomarker discovery and targets for therapeutic development.
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