Objective:

To evaluate GBA1 variants classified as "unknown" in order to clarify their contribution to PD risk and inform genetic stratification in clinical trials.

Background:

Variants in the GBA1 gene, which cause Gaucher’s disease (GD) in biallelic forms, are also associated with increased Parkinson’s disease (PD) risk in heterozygous carriers. While carriers of GBA1 variants classified as severe or mild (causing GD type 1 or GD types 2 and 3, respectively) can enroll in clinical trials, carriers of variants classified as "unknown" are typically excluded.

Design/Methods:

We performed a meta-analysis of 34 case–control studies including 24,060 PD cases and 14,465 controls. Odds ratios (ORs) were estimated using random-effects models with a constant continuity correction of 0.5. The American College of Medical Genetics (ACMG) criteria were applied for further stratification.

Results:

When analyzed together without stratification, GBA1 variants of "unknown" GD status were not significantly associated with Parkinson’s disease (OR = 1.34, 95% CI: 0.93–1.93; I² = 52.4%). However, when these variants were further classified by ACMG criteria, significant associations emerged. GBA1 variants of unknown status that were also classified as variants of uncertain significance (VUS) by ACMG were associated with PD (OR = 1.59, 95% CI: 1.25–2.02; I² = 0%). The association persisted when VUS, likely pathogenic, and pathogenic categories were analyzed in combination (OR = 1.63, 95% CI: 1.28–2.06; I² = 0%).

Conclusions:

GBA1 variants classified as "unknown" may be considered with caution for inclusion in PD clinical trials if they are also categorized by ACMG as VUS, likely pathogenic, or pathogenic.