Objective: To identify genetic risk modifiers for GBA1 risk variant carriers of European and African ancestry, we used  data from GP2 (http://gp2.org/), the UK Biobank, and other datasets. We examined how GBA1 variants interact with genetic factors influencing PD risk and progression.

Background: The GBA1 variants p.E326K, p.T369M, and p.N370S substantially increase Lewy body disease risk, yet, in the context of risk, the interaction of these variants with other genetic factors remain underexplored. Prior work showed GBA1 carriers’ PD risk is modified by polygenic risk score (PRS), with variability in SNCA identified as modifiers, and that higher PRS associates with increased risk and earlier onset, highlighting the importance of genetic modifiers.

Method: We designed a carrier-specific GWAS framework extracting GBA1 carriers separately by variant: p.N370S, p.T369M, and p.E326K in European ancestries; and rs3115534 in African ancestries. Following genotype harmonization, we ran carrier-only GWASes using fixed effects models and meta-analyzed across cohorts to detect variant-specific and general modifiers. We also tested PRS influence on GBA1-associated risk and age at onset.

Results: Variant-specific analyses in European carriers show attenuated, suggestive signals (p < 1E-6), with none reaching genome-wide significance (5E-8), consistent with reduced power per subset. The combined meta-analysis replicates the previously reported SNCA modifier signal (rs356182), and the remaining five signals fall near known PD loci.

Conclusion: GBA1 carrier PD risk is influenced by variants at known PD loci, most notably SNCA. Variant-specific signals are suggestive, consistent with reduced power per subset. No genome-wide significant modifiers were identified in African/admixed ancestry carriers at this stage. These findings aim to refine PD genetic models and guide precision counseling and therapeutic strategies. Dual carriers of GBA1 and LRRK2 add complexity with ~6% of GP2 European LRRK2 carriers also carrying a GBA1 variant. We will also formally test interaction effects, characterize dual carriers, and validate rare variants using WGS.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/genome-wide-discovery-of-gba1-modifiers-in-parkinsons-disease-carriers-across-populations-from-the-global-parkinsons-genetics-program/