Common and rare GCH1 variants are associated with Parkinson's disease.

TitleCommon and rare GCH1 variants are associated with Parkinson's disease.
Publication TypeJournal Article
Year of Publication2019
AuthorsRudakou, U, Bencheikh, BOuled Amar, Ruskey, JA, Krohn, L, Laurent, SB, Spiegelman, D, Liong, C, Fahn, S, Waters, C, Monchi, O, Fon, EA, Dauvilliers, Y, Alcalay, RN, Dupré, N, Gan-Or, iv, Z
JournalNeurobiol Aging
Date Published2019 Jan

GCH1 encodes the enzyme guanosine triphospahte (GTP) cyclohydrolase 1, essential for dopamine synthesis in nigrostriatal cells, and rare mutations in GCH1 may lead to Dopa-responsive dystonia (DRD). While GCH1 is implicated in genomewide association studies in Parkinson's disease (PD), only a few studies examined the role of rare GCH1 variants in PD, with conflicting results. In the present study, GCH1 and its 5' and 3' untranslated regions were sequenced in 1113 patients with PD and 1111 controls. To examine the association of rare GCH1 variants with PD, burden analysis was performed. Three rare GCH1 variants, which were previously reported to be pathogenic in DRD, were found in five patients with PD and not in controls (sequence Kernel association test, p = 0.024). A common haplotype, tagged by rs841, was associated with a reduced risk for PD (OR = 0.71, 95% CI = 0.61-0.83, p = 1.24 × 10), and with increased GCH1 expression in brain regions relevant for PD ( Our results support a role for rare, DRD-related variants, and common GCH1 variants in the pathogenesis of PD.

Alternate JournalNeurobiol. Aging
PubMed ID30314816
PubMed Central IDPMC6251729
Grant ListK02 NS080915 / NS / NINDS NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States