GALC variants affect Glucocerebrosidase to Galactosylceramidase activity ratio

Abstract

ObjectiveGenes within the lysosomal glycosphingolipid pathway, including GBA1 and GALC, are important genetic risk factors in Parkinsons disease (PD). We hypothesized that PD risk relates not only to individual enzyme effects but also to coordination between glucocerebrosidase (GCase) and galactosylceramidase (GalCase) activities, and examined how genetic variants influence their activity ratio.

MethodsWe studied 1,290 individuals from the Parkinsons Precision Medicine Initiative and Columbia University cohorts with genetic and dried-blood-spot enzymatic data. Genome-wide association analyses of the glucocerebrosidase/galactosylceramidase activity ratio were performed in the combined cohort, by sex, and per cohort, followed by meta-analysis. For lead variants, Pearson correlations between enzyme activities were compared across genotypes, and genotype-by-GCase interactions were tested.

ResultsThe GALC locus was associated with glucocerebrosidase/galactosylceramidase activity ratio in the combined cohort (rs365448; beta=-1.90; P=5.91e-115), replicated across cohorts and meta-analysis (beta = -1.66, P=6.33e-191), and in linkage disequilibrium with the PD GWAS index variant rs979812. This association remained significant in both sexes. Correlation between glucocerebrosidase and galactosylceramidase activities differed by rs979812 genotype (TT r=0.33 versus GG r=0.13; P=0.01), with a significant genotype-by-GCase interaction (P=3.05e-5). Among 134 PD loci examined, ten showed nominal association with the ratio-GWAS, including GBA1, where risk-variant carriers showed a similar pattern, yet not statistically significant.

InterpretationGALC variants influence the balance between glucocerebrosidase and galactosylceramidase activity, and this relationship may differ by genotype at PD-associated variants. These findings suggest PD risk at lysosomal glycosphingolipid genes may partly reflect altered coordination between pathway enzymes rather than isolated single-enzyme effects, warranting functional validation.

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BibTeX RIS

BibTeX

@misc{vajargah2026galc,
  title = {{GALC variants affect Glucocerebrosidase to Galactosylceramidase activity ratio}},
  author = {A. Rajabi Vajargah and K. Senkevich and Z. Zhang and L. Liu and S. Amiri and M. Ghamgosar Shahkhali and M. Teferra and C. Lacarriere-Keita and P. Sardi and M. S. R. Chiang and C. Waters and A. Harroud and R. Alcalay and T. Durcan and E. A. Fon and Z. Gan-Or},
  howpublished = {medRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.05.26364651},
  url = {https://www.medrxiv.org/content/10.64898/2026.10.05.26364651v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - GALC variants affect Glucocerebrosidase to Galactosylceramidase activity ratio
AU  - A. Rajabi Vajargah
AU  - K. Senkevich
AU  - Z. Zhang
AU  - L. Liu
AU  - S. Amiri
AU  - M. Ghamgosar Shahkhali
AU  - M. Teferra
AU  - C. Lacarriere-Keita
AU  - P. Sardi
AU  - M. S. R. Chiang
AU  - C. Waters
AU  - A. Harroud
AU  - R. Alcalay
AU  - T. Durcan
AU  - E. A. Fon
AU  - Z. Gan-Or
PY  - 2026
DA  - 2026/10/05
PB  - medRxiv
DO  - 10.64898/2026.10.05.26364651
UR  - https://www.medrxiv.org/content/10.64898/2026.10.05.26364651v1
AB  - ObjectiveGenes within the lysosomal glycosphingolipid pathway, including GBA1 and GALC, are important genetic risk factors in Parkinsons disease (PD). We hypothesized that PD risk relates not only to individual enzyme effects but also to coordination between glucocerebrosidase (GCase) and galactosylceramidase (GalCase) activities, and examined how genetic variants influence their activity ratio.  MethodsWe studied 1,290 individuals from the Parkinsons Precision Medicine Initiative and Columbia University cohorts with genetic and dried-blood-spot enzymatic data. Genome-wide association analyses of the glucocerebrosidase/galactosylceramidase activity ratio were performed in the combined cohort, by sex, and per cohort, followed by meta-analysis. For lead variants, Pearson correlations between enzyme activities were compared across genotypes, and genotype-by-GCase interactions were tested.  ResultsThe GALC locus was associated with glucocerebrosidase/galactosylceramidase activity ratio in the combined cohort (rs365448; beta=-1.90; P=5.91e-115), replicated across cohorts and meta-analysis (beta = -1.66, P=6.33e-191), and in linkage disequilibrium with the PD GWAS index variant rs979812. This association remained significant in both sexes. Correlation between glucocerebrosidase and galactosylceramidase activities differed by rs979812 genotype (TT r=0.33 versus GG r=0.13; P=0.01), with a significant genotype-by-GCase interaction (P=3.05e-5). Among 134 PD loci examined, ten showed nominal association with the ratio-GWAS, including GBA1, where risk-variant carriers showed a similar pattern, yet not statistically significant.  InterpretationGALC variants influence the balance between glucocerebrosidase and galactosylceramidase activity, and this relationship may differ by genotype at PD-associated variants. These findings suggest PD risk at lysosomal glycosphingolipid genes may partly reflect altered coordination between pathway enzymes rather than isolated single-enzyme effects, warranting functional validation.
ER  -

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