The Role of HbA1c in Parkinson's Disease: An Integrative Analysis by Single-Cell, Bulk Transcriptome and Mendelian Randomization.

Decreased glucose tolerance is recognized as a factor associated with Parkinson's disease (PD) progression, yet the relationship between HbA1c and PD prognosis remains insufficiently explored. Using data from the Integrated Epidemiological Unit (IEU) open Genome-Wide Association Study (GWAS), PD's IEU-b-7 and HbA1c's IEU-b-104 were extracted. RNA-seq data from GSE20292 and single-cell RNA-seq data from GSE157783 were retrieved from Gene Expression Omnibus (GEO). Mendelian Randomization (MR) analysis, with HbA1c as the exposure and PD as the outcome, was performed using the inverse variance weighted (IVW) method. Differentially expressed genes (DEGs) between PD and controls in GSE20292 were identified, and overlapping instrumental variables (IVs) and DEGs pinpointed a set of candidate genes. Machine learning refinement selected biomarkers, leading to the development of a PD biomarker-based nomogram. Key cell lineages in GSE140231 were characterized, and communication and pseudotime analyses explored cell crosstalk and evolution. Using 223 independent single nucleotide polymorphisms (SNPs)as IVs, HbA1c was found causally [IVW: Odds Ratio (OR) = 1.438, P = 0.026, 95% Confidence Interval (CI) = 1.043-1.981].. Among 625 genes associated with these SNPs, 842 DEGs were identified by comparing PD vs. controls, intersecting with 27 candidate genes. Notably, five biomarkers-FASN, MICAL3, TCIRG1, CDK10, and MFSD1-emerged as potential diagnostic targets for PD. The receiver operating characteristic (ROC) curve demonstrated the high diagnostic accuracy of these biomarkers. Analysis of key cell lineages revealed strong interactions between excitatory and inhibitory cells and oligodendrocyte precursor cells and Astrocytes cells. In conclusion, HbA1c is identified as a risk factor for PD, with FASN, MICAL3, TCIRG1, CDK10, and MFSD1 representing promising targets for PD diagnosis and treatment.