Analysis of common and rare VPS13C variants in late-onset Parkinson disease

Uladzislau Rudakou; Jennifer A Ruskey; Lynne Krohn; Sandra B Laurent; Dan Spiegelman; Lior Greenbaum; Gilad Yahalom; Alex Desautels; Jacques Y Montplaisir; Stanley Fahn; Cheryl H Waters; Oren Levy; Caitlin M Kehoe; Sushma Narayan; Yves Dauvilliers; Nicolas Dupré; Sharon Hassin-Baer; Roy N Alcalay; Guy A Rouleau; Edward A Fon; Ziv Gan-Or

doi:10.1212/NXG.0000000000000385

Analysis of common and rare VPS13C variants in late-onset Parkinson disease

Neurol Genet. 2020 Jan 9;6(1):385. doi: 10.1212/NXG.0000000000000385. eCollection 2020 Feb.

Authors

Uladzislau Rudakou¹, Jennifer A Ruskey¹, Lynne Krohn¹, Sandra B Laurent¹, Dan Spiegelman¹, Lior Greenbaum¹, Gilad Yahalom¹, Alex Desautels¹, Jacques Y Montplaisir¹, Stanley Fahn¹, Cheryl H Waters¹, Oren Levy¹, Caitlin M Kehoe¹, Sushma Narayan¹, Yves Dauvilliers¹, Nicolas Dupré¹, Sharon Hassin-Baer¹, Roy N Alcalay¹, Guy A Rouleau¹, Edward A Fon¹, Ziv Gan-Or¹

Affiliation

¹ Department of Human Genetics (U.R., L.K., G.A.R, Z.G.-O.), McGill University, Montréal; Montreal Neurological Institute (U.R., J.A.R., L.K., S.B.L., D.S., G.A.R., E.A.F.Z.G.-O.), McGill University; Department of Neurology and Neurosurgery (J.A.R., S.B.L., D.S., G.A.R., E.A.F., Z.G.-O.), McGill University, Montréal, Québec, Canada; The Danek Gertner Institute of Human Genetics, Sheba Medical Center (L.G.); The Joseph Sagol Neuroscience Center (L.G., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan; Sackler School of Medicine (L.G., G.Y., S.H.-B.), Tel-Aviv University; Department of Neurology (G.Y., S.H.-B.), Sheba Medical Center; Movement Disorders Institute (G.Y., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Centre d'Études Avancées en Médecine du Sommeil (A.D., J.Y.M.), Hôpital du Sacré-Cœur de Montréal; Department of Neurosciences (A.D.), Université de Montréal; Department of Psychiatry (J.Y.M.), Université de Montréal, Québec, Canada; Department of Neurology (S.F., C.H.W., O.L., C.M.K., S.N., R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York; Department of Neurology (Y.D.), National Reference Center for Narcolepsy, Sleep Unit, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm, France; Division of Neurosciences (N.D.), CHU de Québec, Université Laval; Department of Medicine (N.D.), Faculty of Medicine, Université Laval, Québec City, Canada; and Taub Institute for Research on Alzheimer's Disease and the Aging Brain (R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York.

Abstract

Objective: We aimed to study the role of coding VPS13C variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).

Methods: VPS13C and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants 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: No biallelic carriers of rare VPS13C variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding VPS13C variants in PD. A VPS13C haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28-0.82, p = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.

Conclusions: Our results do not support a role for rare heterozygous or biallelic VPS13C variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.

Abstract

Grants and funding