Objective: Trait- or disease-associated genetic variants contribute to substantial variability and penetrance of complex traits and diseases in humans. Several causative genes and risk factors have been identified in familial forms of Parkinson’s disease (PD) but how patient’s genomes shape the predisposition to develop PD remains unclear.

Background: Mutations in LRRK2 are the most common autosomal dominantly inherited cause of PD. The p.G2019S mutation displays incomplete penetrance and affected individuals display a broad range of age at disease onset (AAO). To date, GWAS have failed to identify modifiers of AAO in LRRK2-PD. Identifying such variants and understanding their biological action remain a challenge.

Method: Through whole genome sequencing and segregation analysis in multiple families with p.G2019S LRRK2-associated PD, we have detected rare genetic variants predicted to act as modifiers of AAO and assessed LRRK2 phenotypes in patient iPSC-derived dopaminergic neurons.
Using a new scoring system, we prioritized coding variants acting as AAO modifiers for functional in vitro validation. Among them we find GO term enrichment for genes with association to “neuron projection” but also Golgi apparatus associated vesicle and transport. From the candidates we selected the missense variant p.E432K in VPS41 (a member of the HOPS complex essential in lysosome/endosome trafficking), predicted to confer protective effect on AAO in one of the families analyzed.

Results: We found that VPS41 knockdown (KD) results in neurite outgrowth indistinguishable between p.G2019S and isogenic WT LRRK2 neurons. Lysosome and endosome morphology was altered upon VPS41 KD, independent of LRRK2 status. The overexpression (OE) of WT and p.E432K VPS41 in HEK293T cells showed a differential starvation response, with increased TFE3 nuclear localization under baseline and starved conditions. In contrast, decreased TFE3 protein levels were previously reported in PD postmortem substantia nigra compared to controls.

Conclusion: Our findings lend support the concept of disease modifying variants incrementally contributing to the differential PD risk in the context of LRRK2 mutations. We are further investigating the effects of p.E432K VPS41 OE on neurite outgrowth, endosome/lysosome morphology and TFE3 mediated autophagic response in patient neurons and controls.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/identification-and-functional-characterization-of-genetic-modifier-of-penetrance-in-g2019s-lrrk2-associated-parkinsons-disease-through-family-whole-genome-sequencing/