Using polygenic and transcriptional risk scores to investigate psychiatric and cognitive symptoms in Parkinson’s disease

Psychiatric and cognitive symptoms are commonly observed in individuals with Parkinson’s disease (PD) with a significant impact on quality of life. Given the genetic contribution to PD, cross-trait polygenic risk score (PRS) analysis may elucidate underlying biological mechanisms. Transcriptional risk scores (TRS) – the weighted sum of an individual’s observed gene expression – offer a complementary approach, having shown good prediction in other diseases. Here, we combined transcriptome-wide analysis of Alzheimer’s disease (AD), depression, PD, and schizophrenia with RNA-seq data from the Parkinson’s Progressive Markers Initiative (PPMI) ( N = 592; N _CASES = 431) and 10 years of follow-up data to conduct the first within- and cross-trait TRS study of PD, its severity, psychiatric and cognitive symptoms, and their progression. TRS associations were compared to PRS. Polygenic risk for PD was significantly associated ( p _FDR < 0.05) with PD case/control status. Higher transcriptional risk for PD was not associated with PD case/control status but was associated with greater PD severity at baseline, suggesting they still capture the broader disease burden. Higher transcriptional risk for AD was associated with having PD, greater baseline severity, higher baseline depression, anxiety, hallucinations and a faster increase in both hallucinations and apathy, implicating shared mechanisms across neurodegenerative diseases. Higher polygenic and transcriptional risk for depression was associated with higher baseline depression and anxiety in PD and a faster increase in anxiety over time. Higher transcriptional risk for AD was associated with faster decline across all cognitive domains, while higher transcriptional risk for schizophrenia showed protective effects, suggesting TRS can identify novel biological contributions to cognitive decline, with the potential for targeted interventions. Our findings show that transcriptional and polygenic risk scores capture different aspects of biological contributions to PD symptoms and progression.