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. 2025 Sep;62(9):11560-11571.
doi: 10.1007/s12035-025-04996-1. Epub 2025 Apr 29.

Genome-Wide Association Study of Glucocerebrosidase Activity Modifiers

Emma N Somerville  1   2 , Lynne Krohn  1   2 , Konstantin Senkevich  1   3 , Eric Yu  1   2 , Jamil Ahmad  1   3 , Farnaz Asayesh  1   3 , Jennifer A Ruskey  1   3 , Dan Spiegelman  1   3 , Stanley Fahn  4 , Cheryl Waters  4 , S Pablo Sardi  5 , Roy N Alcalay  4   6 , Ziv Gan-Or  7   8   9
Affiliations

Genome-Wide Association Study of Glucocerebrosidase Activity Modifiers

Emma N Somerville et al. Mol Neurobiol. 2025 Sep.

Abstract

One of the most common genetic risk factors for Parkinson's disease (PD) is variants in GBA1, which encodes the lysosomal enzyme glucocerebrosidase (GCase). GCase deficiency has been associated with an increased PD risk, but not all individuals with low GCase activity are carriers of GBA1 mutations, suggesting other factors may be acting as modifiers. We aimed to discover common variants associated with GCase activity, as well as replicate previously reported associations, by performing a genome-wide association study using two independent cohorts: a Columbia University cohort consisting of 697 PD cases and 347 controls and the Parkinson's Progression Markers Initiative (PPMI) cohort consisting of 357 PD cases and 163 controls. As expected, GBA1 variants have the strongest association with decreased activity, led by N370S (beta = - 4.36, se = 0.32, p = 5.05e - 43). We also identify a novel association in the GAA locus (encoding for acid alpha-glucosidase, beta = - 0.96, se = 0.17, p = 5.23e - 09) that may be the result of an interaction between GCase and acid alpha-glucosidase based on various interaction analyses. Lastly, we show that several PD-risk loci are potentially associated with GCase activity. Further research will be needed to replicate and validate our findings and to uncover the functional connection between acid alpha-glucosidase and GCase.

Keywords: GBA1; Genome-wide association study; Glucocerebrosidase; Lysosomal metabolism; Parkinson’s disease.

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Conflict of interest statement

Declarations. Consent to Publish: All authors have read and consented to publish this manuscript. Competing Interests: Z.G.O received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Ono Therapeutics, Denali, Handl Therapeutics, Neuron23, Bial Biotech, Bial, UCB, Capsida, Vanqua bio, Congruence Therapeutics, Takeda, Jazz Guidepoint, Lighthouse and Deerfield. Ethics Approval and Consent to Participate: Informed consent forms were signed by all participants prior to entering their respective studies, and the study protocol was approved by the institutional review boards.

Figures

Fig. 1
Fig. 1
Manhattan plot of log adjusted p-values at each genomic position in (a) the Columbia cohort with adjustments for age, sex, disease status, Ashkenazi Jewish status, LRRK2 G2019S, ASM activity, GAA activity, GLA activity, GALC activity, and the top 10 PCs; (b) the PPMI cohort with adjustments for age, sex, disease status, LRRK2 G2019S genotype, ASM activity, GAA activity, GLA activity, GALC activity, white blood cell count, and the top 10 PCs; and (c) the meta-analysis of these two analyses
Fig. 2
Fig. 2
Manhattan plot of log adjusted p-values at each genomic position in the Columbia cohort with adjustments for (a) age, sex, disease status, Ashkenazi Jewish status, LRRK2 G2019S, ASM activity, GLA activity, GALC activity, and the top 10 PCs; and (b) age, sex, disease status, Ashkenazi Jewish status, LRRK2 G2019S, GBA1 N370S, GBA1 T369M, GBA1 E326 K, ASM activity, GAA activity, GLA activity, GALC activity, and the top 10 PCs
Fig. 3
Fig. 3
Interaction plots of GCase and acid alpha-glucosidase activity colored by 17:78,061,141:T:G genotype in (a) Columbia and (b) PPMI
See this image and copyright information in PMC

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