OBJECTIVES: Our goal was to investigate the clinical relevance and PD risk associated with the GCH1 p.Ser80Asn variant.

METHODS: We first identified a segregating GCH1 p.Ser80Asn variant in a Malaysian Chinese PD family via whole genome sequencing (WGS). We assessed its risk association using multi-ancestry WGS data from the Global Parkinson's Genetics Program (GP2) (n = 22,372PD vs. n = 8,826Controls) and meta-analysis of East Asian (EAS) cohorts (n = 4,712PD vs. 38,733Controls). Haplotype analyses were performed and clinico-demographic details of affected variant carriers were collated.

RESULTS: The GCH1 p.Ser80Asn variant was enriched in GP2 EAS PD populations (n = 9/2,757; 0.33%), but not detected in other ancestries. Meta-analysis revealed increased PD risk in EAS populations (odds ratio = 5.1; 95% confidence intervals [CI] = 2.3-10.7; P = 2.89 × 10-5). A shared haplotype (~330 kbp) was identified among variant carriers. Affected carriers (mean age at onset: 56.3 ± 12.5 years) had additional occurrence of dystonia, whereas dementia was rare.