Objective: To identify potential genetic risk modifiers for GBA1 variant carriers across genetically determined European ancestries (European, Ashkenazi Jewish, Finnish, and Icelandic) using data from the Global Parkinson’s Genetics Program (GP2, http://gp2.org/), previously published PD GWAS (IPDGC), the Fox Insight Genetics Study (FIGS), and the UK Biobank (UKB). The study aims to further understand the interactions between GBA1 variants and other genetic factors that influence Parkinson’s disease (PD) risks and progression in diverse European populations.

Background: Recent findings from the largest European meta-GWAS by the GP2 have highlighted significant heterogeneity in genetic risk factors for Parkinson’s disease (PD) across different European ancestries. This heterogeneity is likely a result of varied genetic structures and historical migration patterns within Europe. While GBA1 variants like p.E326K, p.T369M, and p.N370S are known to substantially increase the risk of Lewy body diseases, their interactions with other genetic factors across diverse European groups remain underexplored.

Method: We identified any participants from the included cohorts who carried a GBA1 variant (p.E326K, p.T369M, or p.N370S). We then performed a genome-wide association study (GWAS) to identify risk loci that are associated with carrying one of the 3 variants using fixed effects models. We also tested a polygenic risk score (PRS) to assess its influence on GBA1-associated risk and age at onset.

Results: While our analyses are preliminary, we identified several regions where the risk of PD in GBA1 carriers is influenced by specific variants at loci that are known to be associated more generally with PD risk. We anticipate that this analysis will help in understanding the complex interplay of genetic modifiers that influence the phenotype and progression of PD among carriers of GBA1 variants, with potential variations across the different European ancestries studied.

Conclusion: This project aims to extend current knowledge on GBA1-associated PD by identifying genetic modifiers that influence disease risk and progression in diverse European populations. By doing so, we hope to refine the genetic models of PD, improve the precision of genetic counseling, and potentially guide future therapeutic strategies tailored to specific genetic backgrounds.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genetic-risk-modifiers-for-gba1-carriers-in-parkinsons-disease-from-the-global-parkinsons-genetics-program/