Objective: To test the hypothesis of NPC1 to be a PD risk factor gene.

Background: The many etiologies of PD include genetic risk factors. The most prominent of these are certain mono-allelic variants in GBA, the gene that is bi-allelically affected in the recessive lysosomal storage disorder Gaucher disease. A similar role in PD has been hypothesized for mono-allelic variants in NPC1, the gene underlying recessive Niemann-Pick Disease Type C1.

Method: We compiled all NPC1 variants seen in house in ~11,000 panel-sequenced PD patients and/or in a cohort of ~17,000 exome/genome-sequenced controls that were matched according to country of origin. Comparisons considered two types of variants: (i) Niemann-Pick Disease Type C1-associated variants, and (ii) rare (minor allele frequency <0.02) missense variants. Each variant list was analyzed by a variant-level approach and a ‘collapsing to the variant-type level’ approach.

Results: Counts for single variants were too small to justify a statistics analyses approach. At the variant type-level, we found 43 patients vs. 74 controls with heterozygous pathogenic or likely pathogenic NPC1 variants, while NPC1 missense variants were seen in 358 patients vs. in 618 controls. Neither of these observations argues for an enrichment of NPC1 variants of interest in PD patients.

Conclusion: In what we believe is the most extensive study addressing NPC1 in PD, we did not find evidence for the hypothesis of NPC1 to represent a PD risk factor. Our findings are relevant for concepts that aim to elucidate the link between PD and lysosomal dysfunction.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/npc1-is-not-a-pd-risk-factor-gene/