biostudies-literatureSenkevich KCanada First Research Excellence FundNCATS NIH HHSNIA NIH HHSNIDA NIH HHSBrookdale FoundationNIMH NIH HHSMichael J. Fox FoundationCanadian Consortium on Neurodegeneration in AgingNINDS NIH HHSNational Institutes of HealthParkinson’s Foundation1859-1872https://www.ebi.ac.uk/biostudies/studies/S-EPMC10151180biostudies-literatureUnknown146(5)The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression MarkeBrain : a journal of neurologyGALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.PMC10151180R01 AG015819P50 MH096891K02 NS080915P50 AG025711R01 AG036836U01 AG006786U01 AG046139R01 AG032990R01 MH097276U24 NS072026R37 MH057881P01 AG002219P50 MH084051P50 MH084053U01 AG046152P30 AG019610R01 MH085542R01 MH109897R01 MH109677P50 AG005138UL1 TR000040P30 AG010161P50 MH066392P01 AG017216R01 AG018023R01 MH080405P01 AG003949R01 MH075916F31 AG051381U01 MH103392P50 AG016574HHSN271201300031CR01 MH110921R01 AG048015R01 NS080820R01 AG017917R01 MH093725K02NS080915Nikanorova DMonchi ORudakou UWaters CDworkind AGreenbaum LAhmad JYu EBlauwendraat CAlcalay RNSenkevich KAsayesh FRuskey JAVanderperre BHassin-Baer SDauvilliers YZorca CEGrenn FPSardi SPSomerville ESpiegelman DTrempe JFDupre NFahn SChiang MSRGan-Or ZFon EAErmolaev ADurcan TMfalseGALC variants affect galactosylceramidase enzymatic activity and risk of Parkinson's disease.The association between glucocerebrosidase, encoded by GBA, and Parkinson's disease (PD) highlights the role of the lysosome in PD pathogenesis. Genome-wide association studies in PD have revealed multiple associated loci, including the GALC locus on chromosome 14. GALC encodes the lysosomal enzyme galactosylceramidase, which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whether GALC is the gene driving the association in the chromosome 14 locus and, if so, by which mechanism. We first aimed to examine whether variants in the GALC locus and across the genome are associated with galactosylceramidase activity. We performed a genome-wide association study in two independent cohorts from (i) Columbia University; and (ii) the Parkinson's Progression Marke2023-01-01T00:00:00Z2023 May2026-04-15T03:11:16.174Z2025-02-19T02:38:05.432ZS-EPMC101511803637000010.1093/brain/awac413