Objective: To investigate the clinical relevance and PD risk associated with the GCH1 p.Ser80Asn variant.

Background: Heterozygous variants in GCH1 are the most frequent cause of childhood-onset dopa-responsive dystonia (DRD). GCH1 has also been implicated in Parkinson’s disease (PD), but its genotypic spectrum and risk associations are not well defined. Via whole genome sequencing (WGS), we identified a segregating GCH1 p.Ser80Asn variant in a Malaysian Chinese PD family.

Method: We assessed the risk association of GCH1 p.Ser80Asn variant using multi-ancestry WGS data from the Global Parkinson’s Genetics Program (GP2) (n=14,481_PD vs n=7,082_Controls) and meta-analysis of East Asian (EAS) cohorts (n=4,514_PD vs 38,712_Controls). Clinico-demographic details of affected variant carriers were collated.

Results: The GCH1 p.Ser80Asn variant was detected in GP2 EAS PD populations (n=9/2,559, 0.35% in PD; n=1/999, 0.10% in controls) but not in other ancestries. Meta-analysis revealed increased PD risk in EAS populations (odds ratio:5.3; 95%CI:2.4–11.1; p=1.92×10⁻⁵), providing case-control enrichment evidence and allowing reclassification of the variant as likely pathogenic with incomplete penetrance. Among the 13 PD patients with GCH1 p.Ser80Asn variant, they had mean age at onset of 56.3±12.5 years and additional occurrence of dystonia (n=6/13, 46.2%), while dementia was rare (n=1). Only two patients reported a positive family history of PD and none reported a family history of dystonia.

Conclusion: The GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD. This discovery highlights the importance of family studies and ancestral diversity in genetic discovery and suggests that rare, moderate-effect variants may contribute to PD risk architecture.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/association-of-the-gch1-p-ser80asn-variant-with-parkinsons-disease-in-east-asian-populations/