Objective: To study the role of coding VPS13C variants in a large cohort of late-onset PD (LOPD) patients.

Background: VPS13C is within a risk locus for Parkinson Disease (PD) reported in large genome-wide, association studies (GWAS) of European population[1, 2]. Bi-allelicVPS13C mutations are a rare cause of PD with early onset and rapid disease progression[3, 4].

Method: VPS13C and its untranslated regions were sequenced using targeted next-generation sequencing with molecular inversion probes in 1,567 PD patients and 1,667 controls from 3 cohorts. Association tests of rare homozygous and compound heterozygous mutations and burden tests for rare heterozygous mutations were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.

Results: A VPS13Chaplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Qvariants was associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V (OR=0.48, 95%CI=0.28-0.82, p=0.0052).This haplotype was not in linkage disequilibrium (LD) with the known GWAS top hit. There was no statistically significant burden of rare (MAF<1%) or very rare (MAF<0.1%)VPS13C variants in PD. Very rare compound heterozygous mutations were found only in two controls and no rare homozygous mutations were found.

Conclusion: A potentially protective VPS13C coding haplotype was identified in the meta-analysis, not in LD with the top GWAS hit in this locus, suggesting an independent effect. Additional genetic and functional studies are needed to examine the role of this haplotype in PD. Our results do not support a role for rare heterozygous or bi-allelic VPS13C mutations in LOPD.

References: 1. Nalls, M.A., et al., Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat Genet, 2014. 46(9): p. 989-93. 2. Chang, D., et al., A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat Genet, 2017. 49(10): p. 1511-1516. 3. Schormair, B., et al., Diagnostic exome sequencing in early-onset Parkinson’s disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson’s disease. Clin Genet, 2018. 93(3): p. 603-612. 4. Lesage, S., et al., Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy. Am J Hum Genet, 2016. 98(3): p. 500-513.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-coding-vps13c-haplotype-is-associated-with-reduced-risk-for-parkinson-disease/