GCH1 p. Ser80Asn Confers Risk for Parkinson's Disease in East Asian Populations

Introduction GCH1 has been implicated in Parkinson's disease (PD), but its risks variants and associations are not well defined. 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 = 22,372 PD vs. n = 8,826 Controls ) and meta‐analysis of East Asian (EAS) cohorts (n = 4,712 PD vs. 38,733 Controls ). 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. Conclusions The GCH1 p.Ser80Asn variant is a rare, EAS‐enriched risk variant for PD.