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TitleAnalysis of common and rare variants in late-onset Parkinson disease.
Publication TypeJournal Article
Year of Publication2020
AuthorsRudakou, Uladzislau, 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, and Ziv Gan-Or
JournalNeurol Genet
Date Published2020 Feb

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

Methods: 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 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 variants in PD. A 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, = 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 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.

Alternate JournalNeurol Genet
PubMed ID32042909
PubMed Central IDPMC6984134
Grant ListK02 NS080915 / NS / NINDS NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States