Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers

Sir, We read with great interest the study titled ‘Parkinson’s disease in GTP cyclohydrolase 1 mutation carriers’ in the September edition of Brain (Mencacci et al. , 2014). The study demonstrates loss-of-function variants in the GCH1 gene are not only a major cause of DOPA-responsive dystonia but are also enriched in relatives with adult-onset parkinsonism. Furthermore, the authors identify, through exome re-sequencing, a number of GCH1 variants that are enriched in patients with Parkinson’s disease compared to control subjects. This elegant study demonstrates the power of exome re-sequencing and highlights the potential role for rare variants in genes such as GCH1 as susceptibility factors in Parkinson’s disease. A genetic role for the GCH1 locus is reinforced by the recent discovery that a SNP at the GCH1 locus is associated with Parkinson’s disease in a large-scale genome-wide association study (GWAS) meta-analysis (Nalls et al. , 2014). The coding variants identified in the exome re-sequencing study increased the risk of Parkinson’s disease by 7.5-fold (2.4–25.3, 95% confidence intervals) and the authors note that this is likely to be an underestimation of the true odds ratio, because of the method of implementing …