The Relationship of Peripheral Glycoprotein Nonmetastatic Melanoma Protein B and Parkinson's Disease: Insights From a Mendelian Randomization Study.

BACKGROUND

Genome-wide association studies (GWASs) have revealed that glycoprotein nonmetastatic melanoma Protein B (GPNMB) was associated with Parkinson's disease (PD). GPNMB has been found in plasma and cerebrospinal fluid, and its levels and the variation of single nucleotide polymorphisms (SNPs) have been linked to disease severity in PD patients. However, whether the altered expression of GPNMB is the cause or the result cannot be identified in the patient samples.

METHODS

This study applied a Mendelian randomization analysis to explore the causal relationship between GPNMB and PD. The blood GPNMB mRNA level from the expression quantitative trait loci (eQTL) dataset and the plasma GPNMB protein level from the protein quantitative trait loci (pQTL) acted as the exposure. PD's GWAS dataset from the International Parkinson's Disease Genomics Consortium including 33674 PD cases and 449056 normal controls was applied as the outcome.

RESULTS

MR analysis with the inverse-variant weighted method (IVW, OR = 1.416, p = 1.39e - 06) and the weighted median methods (WM, OR = 1.430, p = 4.47e - 07) showed that the plasma GPNMB protein expression was linked to a higher risk of PD. We also discovered a significant association between the blood mRNA level of GPNMB and PD risk. The IVW (OR = 1.243, p = 3.64e - 09) and WM (OR = 1.237, p = 5.11e - 08) methods share similar results. Secondary MR analysis further reveals causality between GPNMB pQTL/eQTL and brain volume traits.

CONCLUSIONS

The study demonstrated a significant association between plasma GPNMB protein (pQTL) and mRNA level (eQTL) with PD. Further secondary MR analysis revealed causality between GPNMB pQTL/eQTL and brain volume traits.