Expanding causal genes for Parkinson's disease via multi-omics analysis

Abstract

Genome‑wide association studies (GWASs) have revealed numerous loci associated with Parkinson's disease (PD). However, some potential causal/risk genes were still not revealed and no etiological therapies are available. To find potential causal genes and explore genetically supported drug targets for PD is urgent. By integrating the expression quantitative trait loci (eQTL) and protein quantitative trait loci (pQTL) datasets from multiple tissues (blood, cerebrospinal fluid (CSF) and brain) and PD GWAS summary statistics, a pipeline combing Mendelian randomization (MR), Steiger filtering analysis, Bayesian colocalization, fine mapping, Protein-protein network and enrichment analysis were applied to identify potential causal genes for PD. As a result, GPNMB displayed a robust causal role for PD at the protein level in the blood, CSF and brain, and transcriptional level in the brain, while the protective role of CD38 (in brain pQTL and eQTL) was also identified. We also found inconsistent roles of DGKQ on PD between protein and mRNA levels. Another 9 proteins (CTSB, ARSA, SEC23IP, CD84, ENTPD1, FCGR2B, BAG3, SNCA, FCGR2A) were associated with the risk for PD based on only a single pQTL after multiple corrections. We also identified some proteins' interactions with known PD causative genes and therapeutic targets. In conclusion, this study suggested GPNMB, CD38, and DGKQ may act in the pathogenesis of PD, but whether the other proteins involved in PD needs more evidence. These findings would help to uncover the genes underlying PD and prioritize targets for future therapeutic interventions.

Fig. 1. Heatmap of MR results.

Heatmap showing the P values of the shared genes identified by PD GWAS, brain pQTL MR analysis, and eQTL MR analysis and blood eQTL MR analysis. This figure shows the specific pipline and the data set involved in this study.

Fig. 2. The Protein-protein interaction network using MR-identified proteins passed multiple corrections and PD causative/risk genes, or PD drug targets.

a The Protein–protein interaction network using MR-identified proteins passed multiple correction and PD causative/risk genes. The black arrow means MR-identified proteins passed multiple corrections. b The Protein–protein interaction network using MR-identified proteins passed multiple correction and PD drug targets. The red arrow means Drug targets that interact with MR-identified proteins passed multiple corrections.

Fig. 3

The design flow of the study.