Causal role of myeloid cells in Parkinson's disease: Mendelian randomization study

Abstract

Background: Previous studies have observed elevated myeloid cells in the peripheral blood of patients with Parkinson's disease (PD), but the causal relationship between them remains to be elucidated. We investigated whether there is a causal relationship between different subtypes of peripheral blood myeloid cells and PD using Mendelian randomization (MR) combined with bioinformatics analysis. Exploring the etiology of PD from the perspective of genetics can remove confounding factors and provide a more reliable theoretical basis for elucidating the pathogenesis of PD.

Methods: Comprehensive two-sample MR analysis and sensitivity analyses were conducted to explore the causal associations between 64 myeloid cell signatures and PD risk. The Venn diagram and protein-protein interaction network analysis of instrumental variables (IV) corresponding genes were used to further investigate the potential mechanism of myeloid cells influencing the pathogenesis of PD.

Results: We investigated the impact of four immunophenotypes on the risk of PD, including Im MDSC% CD33dim HLA DR^- CD66b^- (relative count), CD33dim HLA DR⁺ CD11b⁺% CD33^dim HLA DR⁺ (relative count), and CD11b on Mo MDSC (MFI) and CD11b on CD33br HLA DR⁺ CD14^dim (MFI), while an immunophenotype's protective effect on PD was observed CD45 on Im MDSC (MFI). The results of bioinformatics analysis showed that CD33, NTRK2, PLD2, GRIK2 and RELN had protein interactions with the risk genes of PD.

Conclusions: Our study has demonstrated a close genetic correlation between different subtypes of myeloid cells and PD, providing guidance for early identification and immunotherapeutic development in patients with PD.

Keywords: Causal inference; Mendelian randomization analysis; Myeloid cells; Parkinson’s disease.