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Updated: Jul 30, 2025
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk
Orly Goldstein1, Mali Gana-Weisz1, Sandro Banfi2
1Laboratory of Biomarkers and Genomics of Neurodegeneration, Neurological Institute, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Objectives:
VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD.
Methods:
77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n = 1200) and stratified manner (LRRK2-G2019S-PD patients (n = 145), GBA-PD patients (n = 235), and non-carriers of these mutations (NC, n = 787)).
Results:
Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios = 2.71, 5.32, 3.26. and 2.19 with p = 0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR = 3.69, p = 0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR = 5.45, p = 0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR = 2.48 and 2.06, with p = 0.022 and 0.0163, respectively).
Conclusions:
Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.
Insights
Genetic variants in vesicle transport genes, including PIK3C3, may modify Parkinson's disease (PD) risk, particularly in LRRK2-G2019S carriers. These findings suggest an oligogenic effect influencing PD susceptibility based on genetic background.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- VPS35 and VPS13 gene variants are linked to Parkinson's disease (PD), with a shared yeast phenotype of abnormal vacuolar transport.
- Investigating additional genes with similar functions may reveal novel risk factors or modifiers for PD.
Purpose of the Study:
- To identify genetic variants in VPS and related genes that modify the risk for Parkinson's disease (PD).
- To analyze the association of these variants with PD in different genetic subgroups, including LRRK2-G2019S and GBA mutation carriers.
Main Methods:
- Whole-genome sequencing data from 202 Ashkenazi Jewish (AJ) PD patients were analyzed for 77 VPS and related genes.
- Ten identified variants in nine genes were genotyped in 1200 AJ PD patients and compared to a control database.
- Allele frequencies and odds ratios were calculated for un-stratified and stratified analyses based on LRRK2-G2019S, GBA mutations, and non-carrier status.
Main Results:
- Five variants in PIK3C3, VPS11, AP1G2, HGS, and VPS13D were significantly associated with PD risk.
- PIK3C3-R768W showed a significant association across all analyses, with the highest odds ratio in LRRK2-G2019S carriers (OR=5.32).
- Other variants demonstrated significant associations within specific subgroups: AP1G2-R563W in LRRK2 carriers, VPS13D-D2932N in GBA carriers, and VPS11-C846G/HGS-S243Y in non-carriers.
Conclusions:
- Variants in vesicle-mediated transport, autophagy, and mitophagy pathways may modify PD risk depending on the patient's genetic background (LRRK2, GBA).
- The PIK3C3-R768W variant is a significant PD-risk allele, especially in LRRK2-G2019S carriers, suggesting an oligogenic effect.
- Further research into the mechanisms of these variants and their interactions is crucial for developing targeted PD prevention and treatment strategies.
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