Abstract Details

Title Meta-analysis of GBA1 Variants With "Unknown" Gaucher Disease Classification in Parkinson’s Disease

Topic Movement Disorders

Presentation(s) P11 - Poster Session 11 (11:45 AM-12:45 PM)

Poster/Presentation
Number 16-013

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.

Authors/Disclosures
Sitki C. Parlar, BSc PRESENTER	Mr. Parlar has nothing to disclose.
Ian Lee, MD	Dr. Lee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Monteris. Dr. Lee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic.
Ziv Gan-Or, MD, PhD (McGill University)	Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neuron23. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Idorsia. Dr. Gan-Or has received personal compensation in the range of $0-$499 for serving as a Consultant for Lighthouse. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Therapeutics. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Gan-Or has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Handl Therapeutics. Dr. Gan-Or has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bial Biotech.

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