Transcriptomic imputation of genetic risk variants uncovers novel whole-blood biomarkers of Parkinson’s disease

Abstract

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.