GPNMB confers risk for Parkinson’s disease through interaction with alpha-synuclein

Many risk loci for Parkinson’s disease (PD) have been identified by genome-wide association studies (GWAS), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel SNP rs199347) to GPNMB, through colocalization analyses of expression quantitative trait locus (eQTL) and PD risk signals, confirmed by allele-specific expression studies in human brain. In cells, Glycoprotein Nonmetastatic Melanoma Protein B protein (GPNMB) co-immunoprecipitated and co-localized with alpha-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of GPNMB resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 781 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating with disease severity. Thus, GPNMB represents a PD risk gene, with potential for biomarker development and therapeutic targeting. Differential gene expression analysis of RNA-seq of iPSC neurons; WT iPSC neurons compared to heterozygous (Het) and homozygous (KO) loss of GPNMB on days 0 and 14 of differentiation. There were in total 30 RNA samples: 3 genotypes (WT, Het and KO) x 2 differentiation time (days 0 and 14) x 5 biological replicates.