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

Neurobiol Aging. 2019 Jan;73:231.e1-231.e6. doi: 10.1016/j.neurobiolaging.2018.09.008. Epub 2018 Sep 15.


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 × 10-4), 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.

Keywords: Dopa-responsive dystonia (DRD); GCH1; GTP cyclohydrolase 1 deficiency; Parkinson disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Brain / metabolism
  • Dystonic Disorders / congenital
  • Dystonic Disorders / genetics
  • Female
  • GTP Cyclohydrolase / genetics*
  • GTP Cyclohydrolase / metabolism
  • Gene Expression
  • Genetic Association Studies*
  • Genetic Variation / genetics*
  • Humans
  • Male
  • Middle Aged
  • Parkinson Disease / genetics*
  • Phenylketonurias / genetics


  • GCH1 protein, human
  • GTP Cyclohydrolase

Supplementary concepts

  • Hyperphenylalaninemia, BH4-Deficient, B
  • Segawa syndrome, autosomal recessive