Objective: To identify rare variant modifiers of GBA1-associated Parkinson’s disease (PD) penetrance among lysosomal storage disorder (LSD) genes.

Background: GBA1 is the most common large-effect PD genetic risk factor, yet most carriers never develop disease. LSD genes operate in shared lysosomal pathways with GBA1, making them candidate penetrance modifiers. Prior screens detected aggregate LSD gene enrichment in GBA1-PD but did not resolve individual modifier genes, and no study has tested whether genetic modification is allele-specific.

Method: We performed a case-only rare variant burden screen of 48 LSD genes in the Global Parkinson’s Genetics Program (GP2) whole-genome sequencing (WGS) data (1394 GBA1-PD, 7224 other PD). Replication used GP2 clinical exome, GP2 NeuroBooster array, and UK Biobank WGS data (2534 GBA1-PD, 29778 other PD). Results were stratified by GBA1 variant (E365K, T408M, N409S). NPC2 protein was quantified via UK Biobank proteomics.

Results: We identified NPC2 (Niemann-Pick type C2) as a GBA1-specific modifier (OR=2.29 [1.42–3.7], p=7.19×10⁻⁴), driven by splice donor variant c.441+1G>A. The interaction was allele-specific: significant for T408M/N409S carriers (OR=2.40 [1.68–3.42], p=1.59×10⁻⁶, I²=0) but absent for E365K (OR=1.21 [0.77–1.90], p=0.639, Figure). NPC2 had no independent PD association, consistent with a pure penetrance modifier. Full interaction analysis demonstrated both multiplicative and super-additive risk, with NPC2 tripling the OR associated with GBA1 T408M/N409S (OR=3.24 [1.4–7.49], p=0.006). Heterozygous and homozygous c.441+1G>A carriers showed 38% and 75% reduction in circulating NPC2 protein respectively, consistent with a hypomorphic allele. Two-sample Mendelian randomization using NPC2 nonsynonymous variants supported a causal relationship between reduced NPC2 protein and increased GBA1-PD risk (p = 1.09×10⁻⁴). Pathway-level analysis revealed differential LSD gene burden after NPC2 exclusion (SKAT p=6.25×10⁻⁴), driven by glycosphingolipid catabolism and mucopolysaccharidosis genes.

Conclusion: NPC2 is a novel modifier of GBA1-PD penetrance and the first demonstrated epistatic interaction between two LSD genes in PD. The allele-specificity of the interaction provides human genetic evidence for mechanistic heterogeneity across GBA1 variants, supporting variant-specific stratification in GBA1-PD trials and identifying lysosomal cholesterol trafficking as a candidate therapeutic target.

GBA1-NPC2 interaction by variant

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MDS Abstracts - https://www.mdsabstracts.org/abstract/npc2-is-an-allele-specific-modifier-of-gba1-associated-parkinsons-disease-risk/