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

Abstract

IntroductionGCH1 has been implicated in Parkinsons disease (PD), but its risks variants and associations are not well defined. ObjectivesTo investigate the clinical relevance and PD risk associated with the GCH1 p.Ser80Asn variant. MethodsWe 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 Parkinsons Genetics Program (GP2) (n=22,372PD vs n=8,826Controls) and meta-analysis of East Asian (EAS) cohorts (n=4,712PD vs 38,733Controls). Clinico-demographic details of affected variant carriers were collated. ResultsThe 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%CI:2.3-10.7; p=2.89x10-5). Affected carriers (mean age at onset:56.3{+/-}12.5 years) had additional occurrence of dystonia, while dementia was rare. ConclusionsThe GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD.