Blood-based gene expression signatures could potentially be used as biomarkers for PD. However, it is unclear whether genetically-regulated transcriptomic signatures can provide novel gene candidates for use as PD biomarkers. We leveraged on the Genotype-Tissue Expression (GTEx) database to impute whole-blood transcriptomic expression using summary statistics of three large-scale PD GWAS. A random forest classifier was used with the consensus whole-blood imputed gene signature (IGS) to discriminate between cases and controls. Outcome measures included Area under the Curve (AUC) of Receiver Operating Characteristic (ROC) Curve. We demonstrated that the IGS (n = 37 genes) is conserved across PD GWAS studies and brain tissues. IGS discriminated between cases and controls in an independent whole-blood RNA-sequencing study (1176 PD, 254 prodromal, and 860 healthy controls) with mean AUC and accuracy of 64.8% and 69.4% for PD cohort, and 78.8% and 74% for prodromal cohort. PATL2 was the top-performing imputed gene in both PD and prodromal PD cohorts, whose classifier performance varied with biological sex (higher performance for males and females in the PD and prodromal PD, respectively). Single-cell RNA-sequencing studies (scRNA-seq) of healthy humans and PD patients found PATL2 to be enriched in terminal effector CD8+ and cytotoxic CD4+ cells, whose proportions are both increased in PD patients. We demonstrated the utility of GWAS transcriptomic imputation in identifying novel whole-blood transcriptomic signatures which could be leveraged upon for PD biomarker derivation. We identified PATL2 as a potential biomarker in both clinical and prodromic PD.

基于血液的基因表达特征有可能用作帕金森病的生物标志物。然而，尚不清楚基因调控的转录组特征是否可以提供用作 PD 生物标志物的新候选基因。我们利用基因型组织表达 (GTEx) 数据库，使用三个大规模 PD GWAS 的汇总统计来估算全血转录组表达。随机森林分类器与一致的全血推算基因签名（IGS）一起使用来区分病例和对照。结果测量包括接受者操作特征 (ROC) 曲线的曲线下面积 (AUC)。我们证明 IGS（ n = 37 个基因）在 PD GWAS 研究和脑组织中是保守的。 IGS 在一项独立的全血 RNA 测序研究（1176 名 PD、254 名前驱对照和 860 名健康对照）中区分了病例和对照，PD 队列的平均 AUC 和准确度分别为 64.8% 和 69.4%，PD 队列的平均 AUC 和准确度为 78.8% 和 74%。前驱期队列。 PATL2是 PD 和前驱 PD 队列中表现最好的推算基因，其分类性能随生物性别的不同而变化（在 PD 和前驱 PD 中，男性和女性的表现分别较高）。对健康人和 PD 患者的单细胞 RNA 测序研究 (scRNA-seq) 发现PATL2在末端效应 CD8+ 和细胞毒性 CD4+ 细胞中富集，其比例在 PD 患者中均有所增加。我们展示了 GWAS 转录组插补在识别新的全血转录组特征方面的实用性，这些特征可用于 PD 生物标志物的推导。我们将PATL2确定为临床和前驱 PD 的潜在生物标志物。