GBA1 Variants with Unknown Classification Are Modest Contributors to Parkinson's Disease Susceptibility

Background GBA1 variants cause Gaucher's disease (GD) in biallelic forms and increase Parkinson's disease (PD) risk in heterozygous carriers. Carriers of mild or severe variants (causing GD type 1 or types 2–3) can enroll in clinical trials, whereas those with GBA1 variants classified as unknown are typically excluded. Objective We assessed the contribution of unknown variants to PD risk and their relevance for trial stratification. Methods We meta‐analyzed 34 case–control studies (24,060 PD cases, 14,465 controls). Odds ratios (ORs) were estimated using random‐effects models and stratified by the American College of Medical Genetics and Genomics (ACMG) criteria. Results Unknown variants also classified as variants of uncertain significance (VUSs) per ACMG criteria were associated with PD (OR = 1.59, 95% confidence interval [CI]: 1.25–2.02; I 2 = 0%). VUSs + likely pathogenic + pathogenic also showed an association (OR = 1.63, 95% CI: 1.28–2.06; I 2 = 0%). Conclusions Unknown GBA1 variants may be considered provisionally in clinical trials if also classified as VUS, likely pathogenic, or pathogenic per ACMG criteria.