QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Acta Neuropathol Commun. 2024 Aug 13;12(1):130. doi: 10.1186/s40478-024-01841-9.
Optical coherence tomography (OCT) is a non-invasive technique to measure retinal layer thickness, providing insights into retinal ganglion cell integrity. Studies have shown reduced retinal nerve fibre layer (RNFL) and ganglion cell inner plexiform layer (GCIPL) thickness in Parkinson's disease (PD) patients. However, it is unclear if there is a common genetic overlap between the macula and peripapillary estimates with PD and if the genetic risk of PD is associated with changes in ganglion cell integrity estimates in young adults.
Western Australian young adults underwent OCT imaging. Their pRNFL, GCIPL, and overall retinal thicknesses were recorded, as well as their longitudinal changes between ages 20 and 28. Polygenic risk scores (PRS) were estimated for each participant based on genome-wide summary data from the largest PD genome-wide association study conducted to date. We further evaluated whether PD PRS was associated with changes in thickness at a younger age. To evaluate the overlap between retinal integrity estimates and PD, we annotated and prioritised genes using mBAT-combo and performed colocalisation through the GWAS pairwise method and HyPrColoc. We used a multi-omic approach and single-cell expression data of the retina and brain through a Mendelian randomisation framework to evaluate the most likely causal genes. Genes prioritised were analysed for missense variants that could have a pathogenic effect using AlphaMissense.
We found a significant association between the Parkinson's disease polygenic risk score (PD PRS) and changes in retinal thickness in the macula of young adults assessed at 20 and 28 years of age. Gene-based analysis identified 27 genes common to PD and retinal integrity, with a notable region on chromosome 17. Expression analyses highlighted NSF, CRHR1, and KANSL1 as potential causal genes shared between PD and ganglion cell integrity measures. CRHR1 showed consistent results across multiple omics levels.
Our findings suggest that retinal measurements, particularly in young adults, could be a potential marker for PD risk, indicating a genetic overlap between retinal structural integrity and PD. The study highlights specific genes and loci, mainly on chromosome 17, as potential shared etiological factors for PD and retinal changes. Our results highlight the importance of further longitudinal studies to validate retinal structural metrics as early indicators of PD predisposition.
光学相干断层扫描（OCT）是一种非侵入性技术，可用于测量视网膜层厚度，提供有关视网膜神经节细胞完整性的信息。研究表明，帕金森病（PD）患者的视网膜神经纤维层（RNFL）和神经节细胞内丛状层（GCIPL）厚度减少。然而，尚不清楚黄斑和视盘周围估计值与 PD 之间是否存在常见的遗传重叠，以及 PD 的遗传风险是否与年轻人的神经节细胞完整性估计值的变化有关。
西澳大利亚州的年轻成年人接受了 OCT 成像。记录了他们的 pRNFL、GCIPL 和整体视网膜厚度，以及他们在 20 岁至 28 岁之间的纵向变化。根据迄今为止进行的最大 PD 全基因组关联研究的全基因组汇总数据，为每位参与者估算了多基因风险评分（PRS）。我们进一步评估了 PD PRS 是否与年轻时的厚度变化有关。为了评估视网膜完整性估计值与 PD 之间的重叠，我们使用 mBAT-combo 对基因进行注释和优先级排序，并通过 GWAS 成对方法和 HyPrColoc 进行共定位。我们使用多组学方法和通过孟德尔随机化框架的视网膜和大脑的单细胞表达数据来评估最可能的因果基因。通过 AlphaMissense 分析了可能具有致病性影响的错义变体的优先级基因。
我们发现帕金森病多基因风险评分（PD PRS）与 20 岁和 28 岁时年轻成年人黄斑区视网膜厚度的变化之间存在显著关联。基于基因的分析确定了 27 个与 PD 和视网膜完整性相关的基因，其中在 17 号染色体上有一个显著区域。表达分析突出了 NSF、CRHR1 和 KANSL1 作为 PD 和神经节细胞完整性测量值之间的潜在因果基因。CRHR1 在多个组学水平上均表现出一致的结果。
我们的研究结果表明，视网膜测量，特别是在年轻人中，可能是 PD 风险的潜在标志物，表明视网膜结构完整性和 PD 之间存在遗传重叠。该研究强调了特定基因和基因座，主要在 17 号染色体上，作为 PD 和视网膜变化的潜在共同发病因素。我们的研究结果强调了进一步进行纵向研究以验证视网膜结构指标作为 PD 易感性的早期指标的重要性。
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