A Comprehensive Study of Circulating Blood Linear RNA nominates CD55 and DLD as novel causal genes and early-stage biomarkers for Parkinson’s Disease

We leveraged transcriptomic data from 4,343 participants from four independent datasets to robustly identify and annotate circulating PD-associated transcripts. We identified 296 differentially expressed transcripts, 28 of which were transcribed from known PD-associated loci. Further, we found a significant overlap between our findings and transcripts dysregulated in brain, as well as proteins differentially accumulated in CSF. Expression of the identified transcripts was affected by genetic background including ancestry and PD-related mutations, and nearly half of the identified transcripts were dysregulated before symptom onset. The differentially expressed transcripts were utilized to develop three predictive models that distinguished between PD and healthy controls with a ROC AUC of 0.727-0.733. The predictive models were capable of detecting PD transcriptomic signatures even before symptom onset. One transcript, DLD, showed particular promise as an early stage, minimally invasive PD biomarker that was differentially expressed in whole blood, brain and CSF. This transcript significantly related to PD in the eQTL analyses and in two of the three predictive models.