Background GBA1 variants cause Gaucher disease (GD) in biallelic forms and increase Parkinson's 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. Objectives 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 (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; I^2=0%). VUS + likely pathogenic + pathogenic also showed association (OR=1.63, 95%CI:1.28-2.06; I^2=0%). Conclusions 'Unknown' GBA1 variants may be considered in clinical trials if also classified as VUS, likely pathogenic, or pathogenic per ACMG criteria.

S.C.P and Y.L. have nothing to report. Z. G.-O. received consultancy fees from Lysosomal Therapeutics Inc. (LTI), Idorsia, Prevail Therapeutics, Inceptions Sciences (now Ventus), Neuron23, Handl Therapeutics, UCB, Capsida, Vanqua Bio, Congruence Therapeutics, Ono Therapeutics, Denali, Bial Biotech, Bial, EG427, Takeda, Jazz Pharmaceuticals, Guidepoint, Lighthouse, and Deerfield.

This work has been supported through grants from the Galen and Hilary Weston Foundation and the Michael J. Fox Foundation (MJFF). Additionally, the G-Can (GBA1-Canada) Initiative, an open-science collaborative initiative aimed at addressing GBA1 mutation-based Parkinson's disease, has made contributions to this research. G-Can is supported by The Hilary and Galen Weston Foundation, Silverstein Foundation, and J. Sebastian van Berkom and Ghislaine Saucier.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All information relevant to the analyses in this study, including the full list of variants examined and the studies considered, is available in the supplementary files of this article.