Genome-Wide Association Study of Glucocerebrosidase Activity Modifiers

作者：Emma N. Somerville, Lynne Krohn, Konstantin Senkevich, Eric Yu, Jamil Ahmad, Farnaz Asayesh, Jennifer A. Ruskey, Dan Spiegelman, Stanley Fahn, Cheryl Waters, S. Pablo Sardi, Roy N. Alcalay, Ziv Gan‐Or · 发表于：Molecular Neurobiology · 年份：2025 · DOI：10.1007/s12035-025-04996-1 · 被引用次数：3 · 研究领域：Lysosomal Storage Disorders Research、Trypanosoma species research and implications、Autism Spectrum Disorder Research

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.