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We systematically screened common variants linked to PD risk by genome\u2010wide association studies (GWAS) for impact on cerebrospinal fluid (CSF) proteins reflecting lysosomal function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Starting with 525 candidate gene\u2010single nucleotide polymorphism (SNPs) pairs nominated by Mendelian randomization from published PD GWAS, we filtered SNPs for downstream evaluation, based on strength of association with PD and impact on brain gene expression. We genotyped top SNPs in 173 PD participants, adding three SNPs capturing variation at the <jats:italic>TMEM106B<\/jats:italic>, <jats:italic>CTSB<\/jats:italic>, and <jats:italic>RAB29<\/jats:italic> loci, encoding genes with known lysosomal function. In the same 173 individuals, we measured 15 CSF proteins (nine lysosomal proteins and six other proteins implicated in neurodegeneration) by parallel reaction monitoring mass spectrometry. We tested SNPs for association with lysosomal proteins. For our top SNP associating with multiple lysosomal proteins, we characterized expression of its target gene <jats:italic>CAMLG<\/jats:italic> in human brain tissue.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Sixteen SNPs emerged from our analysis of GWAS\u2010nominated loci. Genotypes at rs12657663 (<jats:italic>CAMLG<\/jats:italic>) associated with CSF levels of multiple lysosomal markers (cathepsin F, cathepsin L, hexosaminidase B, and tripeptidyl peptidase I) and genotypes at rs7910668 (<jats:italic>ITGA8<\/jats:italic>) with CSF levels of cathepsin B. The protein encoded by <jats:italic>CAMLG<\/jats:italic>, calcium modulating ligand (CAML), is highly expressed in neurons of multiple human brain regions, with higher expression in Lewy body disease cases.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Systematic analysis of PD risk loci nominates <jats:italic>CAMLG<\/jats:italic> as a neuronally expressed risk gene with effects on lysosomes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.52286","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T04:39:05Z","timestamp":1741754345000},"page":"925-937","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Calcium modulating ligand confers risk for Parkinson's disease and impacts lysosomes"],"prefix":"10.1002","volume":"12","author":[{"given":"Hanwen","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Kargilis","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0766-1496","authenticated-orcid":false,"given":"Thomas","family":"Tropea","sequence":"additional","affiliation":[{"name":"Department of Neurology, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Robinson","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania 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Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivianna M.","family":"Van Deerlin","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Perelman School of Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaj","family":"Blennow","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology University of Gothenburg  Gothenburg Sweden"},{"name":"Clinical Neurochemistry Laboratory Sahlgrenska University Hospital  M\u00f6lndal Sweden"},{"name":"Paris Brain Institute, ICM, Pitie\u2010Salpetriere Hospital Sorbonne University  Paris France"},{"name":"Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Department of Neurology, Institute on Aging and Brain Disorders University of 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