GBA1 variants with unknown classification are modest contributors to Parkinson's disease susceptibility

BackgroundGBA1 variants cause Gaucher disease (GD) in biallelic forms and increase Parkinsons disease (PD) risk in heterozygous carriers. Carriers of severe or mild variants (causing GD type 1 or types 2-3) can enroll in clinical trials, whereas those with unknown variants are typically excluded. ObjectivesWe assessed the contribution of unknown variants to PD risk and their relevance for trial stratification. MethodsWe meta-analyzed 34 case-control studies (24,060 PD cases, 14,465 controls). Odds ratios (OR) were estimated using random-effects models and stratified by the American College of Medical Genetics (ACMG) criteria. Results Unknown variants also classified as variants of uncertain significance (VUS) per ACMG criteria were associated with PD (OR=1.59, 95%CI:1.25-2.02; I2=0%). VUS + likely pathogenic + pathogenic also showed association (OR=1.63, 95%CI:1.28-2.06; I2=0%). Conclusions Unknown GBA1 variants may be considered in clinical trials if also classified as VUS, likely pathogenic, or pathogenic per ACMG criteria.