GALCvariants affect galactosylceramidase enzymatic activity and risk of Parkinson’s disease
Authors: Senkevich Konstantin , Zorca Cornelia E. , Dworkind Aliza , Rudakou Uladzislau , Somerville Emma , Yu Eric , Ermolaev Alexey , Nikanorova Daria , Ahmad Jamil , Ruskey Jennifer A. , Asayesh Farnaz , Spiegelman Dan , Fahn Stanley , Waters Cheryl , Monchi Oury , Dauvilliers Yves , Dupré Nicolas , Greenbaum Lior , Hassin-Baer Sharon , Grenn Francis P. , Ruby Chiang Ming Sum , Sardi S. Pablo , Vanderperre Benoît , Blauwendraat Cornelis , Trempe Jean-François , Fon Edward A. , Durcan Thomas M. , Alcalay Roy N. , Gan-Or Ziv 
Published: May 2022

The association between glucocerebrosidase (GCase), encoded byGBA, and Parkinson’s disease highlights the role of the lysosome in Parkinson’s disease pathogenesis. Genome-wide association studies (GWAS) in Parkinson’s disease have revealed multiple associated loci, including theGALClocus on chromosome 14.GALCencodes the lysosomal enzyme galactosylceramidase (GalCase), which plays a pivotal role in the glycosphingolipid metabolism pathway. It is still unclear whetherGALCis the gene driving the association in the chromosome 14 locus, and if so, by which mechanism.

We first aimed to examine whether variants in theGALClocus and across the genome are associated with GalCase activity. We performed a GWAS in two independent cohorts from a)Columbia University and b)the Parkinson’s Progression Markers Initiative study, followed by a meta-analysis with a total of 976 Parkinson’s disease patients and 478 controls with available data on GalCase activity. We further analyzed the effects of commonGALCvariants on expression and GalCase activity using genomic colocalization methods. Mendelian randomization was used to study whether GalCase activity may be causal in Parkinson’s disease. To study the role of rareGALCvariants we analyzed sequencing data from 5,028 Parkinson’s disease patients and 5,422 controls. Additionally, we studied the functional impact ofGALCknock-out on alpha-synuclein accumulation and on GCase activity in neuronal cell models and performedin silicostructural analysis of commonGALCvariants associated with altered GalCase activity.

The top hit in Parkinson’s disease GWAS in theGALClocus, rs979812, is associated with increased GalCase activity (b=1.2; se=0.06; p=5.10E-95). No other variants outside theGALClocus were associated with GalCase activity. Colocalization analysis demonstrated that rs979812 was also associated with increased GalCase expression. Mendelian randomization suggested that increased GalCase activity may be causally associated with Parkinson’s disease (b=0.025, se=0.007, p=0.0008). We did not find an association between rareGALCvariants and Parkinson’s disease.GALCknockout using CRISPR-Cas9 did not lead to alpha-synuclein accumulation, further supporting that increased rather than reduced GalCase levels may be associated with Parkinson’s disease. The structural analysis demonstrated that the common variant p.I562T may lead to improper maturation of GalCase affecting its activity.

Our results nominateGALCas the gene associated with Parkinson’s disease in this locus and suggest that the association of variants in theGALClocus may be driven by their effect of increasing GalCase expression and activity. Whether altering GalCase activity could be considered as a therapeutic target should be further studied.