biostudies-literatureDiaz-Ortiz MENIA NIH HHSNINDS NIH HHSeabk0637https://www.ebi.ac.uk/biostudies/studies/S-EPMC9870036biostudies-literatureUnknown377(6608)Many risk loci for Parkinson's disease (PD) have been identified by genome-wide association studies (GWASs), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel single-nucleotide polymorphism rs199347) to <i>GPNMB</i> through colocalization analyses of expression quantitative trait locus and PD risk signals, confirmed by allele-specific expression studies in the human brain. In cells, glycoprotein nonmetastatic melanoma protein B (GPNMB) coimmunoprecipitated and colocalized with α-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of <i>GPNMB</i> resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 731 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associatingScience (New York, N.Y.)GPNMB confers risk for Parkinson's disease through interaction with α-synuclein.PMC9870036R01 NS082265U19 AG062418F31 NS113481K23 NS114167R01 NS115139P50 NS053488P30 AG072979Skrinak RTBrody EMJain NCharan RLuk KCUnger TLVan Deerlin VMHan NDiaz-Ortiz MEClark EWeintraub DPosavi MGallagher MDDavila-Rivera RSeo YCarceles Cordon MZack RChen-Plotkin ASAmari NLee EBTropea TFfalseGPNMB confers risk for Parkinson's disease through interaction with α-synuclein.Many risk loci for Parkinson's disease (PD) have been identified by genome-wide association studies (GWASs), but target genes and mechanisms remain largely unknown. We linked the GWAS-derived chromosome 7 locus (sentinel single-nucleotide polymorphism rs199347) to <i>GPNMB</i> through colocalization analyses of expression quantitative trait locus and PD risk signals, confirmed by allele-specific expression studies in the human brain. In cells, glycoprotein nonmetastatic melanoma protein B (GPNMB) coimmunoprecipitated and colocalized with α-synuclein (aSyn). In induced pluripotent stem cell-derived neurons, loss of <i>GPNMB</i> resulted in loss of ability to internalize aSyn fibrils and develop aSyn pathology. In 731 PD and 59 control biosamples, GPNMB was elevated in PD plasma, associating2022-01-01T00:00:00Z2022 Aug2025-04-22T10:14:58.757Z2025-04-05T23:30:13.628ZS-EPMC98700363598104010.1126/science.abk0637