AI Article Synopsis

  • Variants in the GBA gene, which codes for glucocerebrosidase (GCase), are major genetic risk factors for Parkinson's disease (PD), leading to decreased GCase activity.
  • A genome-wide association study was conducted using two cohorts to identify common variants related to GCase activity, confirming known variants and discovering a new link involving the GAA gene, which encodes for acid alpha-glucosidase.
  • The identified associations suggest that other PD-risk loci may also influence GCase activity, indicating a need for further studies to explore these relationships and their functional implications.

Article Abstract

One of the most common genetic risk factors for Parkinson's disease (PD) are variants in , 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 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, variants have the strongest association with decreased activity, led by p.N370S (beta = -4.36, se = 0.32, p = 5.05e-43). We also identify a novel association in the 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11177962PMC
http://dx.doi.org/10.21203/rs.3.rs-4425669/v1DOI Listing

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