BackgroundTranscriptomic changes in the essential tremor (ET)–associated cerebello‐thalamo‐cortical “tremor network” and their association to brain structure have not been investigated.ObjectiveThe aim was to characterize molecular changes associated with network‐level imaging‐derived phenotypes (IDP) found in ET.MethodsWe performed an imaging‐transcriptomic study in British adults using imaging‐genome‐wide association study summary statistics (UK Biobank “BIG40” cohort; n = 33,224, aged 40–69 years). We imputed imaging‐transcriptomic associations for 184 IDPs and analyzed functional enrichment of gene modules and aggregate network‐level phenotypes. Validation was performed in cerebellar‐tissue RNA‐sequencing data from ET patients and controls (n = 55).ResultsAmong 237,896 individual predicted gene expression levels for 6063 unique genes/transcripts, we detected 2269 genome‐wide significant associations (Bonferroni P < 2.102e‐7, 0.95%). These were concentrated in intracellular volume fraction measures of white matter pathways and in genes with putative links to tremor (MAPT, ARL17A, KANSL1, SPPL2C, LRRC37A4P, PLEKHM1, and FMNL1). Whole‐tremor‐network cortical thickness was associated with a gene module linked to mitochondrial organization and protein quality control (r = 0.91, P = 2e‐70), whereas white‐gray T1‐weighted magnetic resonance imaging (MRI) contrast in the tremor network was associated with a gene module linked to sphingolipid synthesis and ethanolamine metabolism (r = −0.90, P = 2e‐68). Imputed association effect sizes and RNA‐sequencing log‐fold change in the validation dataset were significantly correlated for cerebellar peduncular diffusion MRI phenotypes, and there was a close overlap of significant associations between both datasets for gray matter phenotypes (χ2 = 6.40, P = 0.006).ConclusionsThe identified genes and processes are potential treatment targets for ET, and our results help characterize molecular changes that could in future be used for patient treatment selection or prognosis prediction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

中文翻译：

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基因表达与震颤网络结构的关联


背景特发性震颤（ET）相关的小脑丘脑皮质“震颤网络”的转录组变化及其与大脑结构的关联尚未得到研究。目的目的是表征与网络水平成像衍生表型（IDP）相关的分子变化我们在 ET.Methods 中使用成像全基因组关联研究摘要统计数据对英国成年人进行了一项成像转录组学研究（英国生物银行“BIG40”队列；n = 33,224，年龄 40-69 岁）。我们估算了 184 个 IDP 的成像转录组关联，并分析了基因模块的功能富集和聚合网络水平表型。在来自 ET 患者和对照 (n = 55) 的小脑组织 RNA 测序数据中进行了验证。结果在 237,896 个个体的 6063 个独特基因/转录本的预测基因表达水平中，我们检测到 2269 个全基因组显着关联 (Bonferroni P < 2.102e ‐7, 0.95%)。这些集中在白质通路的细胞内体积分数测量以及与震颤假定相关的基因（MAPT、ARL17A、KANSL1、SPPL2C、LRRC37A4P、PLEKHM1 和 FMNL1）中。整个震颤网络皮质厚度与线粒体组织和蛋白质质量控​​制相关的基因模块相关（r = 0.91，P = 2e-70），而震颤中的白灰色 T1 加权磁共振成像（MRI）对比网络与鞘脂合成和乙醇胺代谢相关的基因模块相关（r = -0.90，P = 2e-68）。 验证数据集中的估算关联效应大小和 RNA 测序对数倍数变化与小脑脚扩散 MRI 表型显着相关，并且灰质表型的两个数据集之间的显着关联紧密重叠（χ2 = 6.40，P = 0.006） ).结论所确定的基因和过程是 ET 的潜在治疗靶点，我们的结果有助于表征分子变化，这些变化将来可用于患者治疗选择或预后预测。 © 2024 作者。 《运动障碍》由 Wiley periodicals LLC 代表国际帕金森和运动障碍协会出版。