Objective: This study evaluates protein quantitative trait loci (pQTL) effect of single nucleotide polymorphism (SNP) rs199347 in modulating glycoprotein non-metastatic melanoma protein B (GPNMB) expression and assesses GPNMB as potential biomarker for Parkinson’s disease (PD).

Background: Genome-wide association studies (GWAS) have shown a link between non-coding SNP rs199347 at the GPNMB locus and risk for PD [1]. Although rs199347 is known to be an expression QTL for GPNMB RNA in the central nervous system [2], it is not known whether rs199347 genotype modulates GPNMB protein expression. GPNMB protein levels have been reported to be a biomarker for Gaucher disease, a lysosomal storage disorder caused by GBA mutations [3], which also increase risk for PD [1]; however, the potential use of GPNMB as an idiopathic PD biomarker remains unexplored.

Method: PD patients were selected from the Penn Integrative Neurodegenerative Disease Database (INDD) based on clinical diagnosis, whereas controls had no known neurodegenerative disease. Cohorts were matched by age and sex. Plasma and CSF samples were obtained through the Center for Neurodegenerative Disease Research biobank. GPNMB levels were quantified by ELISA (R&D systems) and rs199347 genotype was determined by NeuroX SNP array or Global Screening array. Data were analyzed by linear or logistic regression, to adjusting for covariates.

Results: rs199347 genotype associated with GPNMB protein levels in the CSF regression (β=0.091 (p=9.34e-05)). GPNMB was significantly elevated in the plasma of PD patients compared to controls (p=0.02), but not in CSF.

Conclusion: Our results suggest that rs199347 is a pQTL for GPNMB CSF levels. Significant elevation of GPNMB in PD patient plasma suggests potential use of GPNMB as a peripheral molecular biomarker for PD. Future studies include validation in additional cohorts and mechanistic studies to understand the mechanism whereby GPNMB levels modulate PD risk.

References: [1] Nalls MA et al., 2014. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nature Genetics46(9):989-93. [2] GTEx Portal (GTEx.org), “eQTL Violin Plot, rs199347” [3] Kramer G et al., 2016. Elevation of glycoprotein nonmetastatic melanoma protein B in type 1 Gaucher disease patients and mouse models. FEBS Open Bio 6(9):902-913.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gpnmb-protein-levels-in-cns-are-modulated-by-pd-risk-variant-rs199347/