GCH1 p.Ser80Asn Confers Risk for Parkinson's Disease in East Asian Populations
Tay, Y. W.; Lee, A. L.; Schee, J. P.; Lin, C. H.; Tan, E. K.; Shin, J. H.; Chen, P.-S.; Fan, S.-P.; Li, C.-H.; Ng, E. Y. L.; Kim, H. J.; Jeon, B.; Koks, S.; Mok, K. Y.; Lim, Y. T.; Kamaruddin, M. S.; Toh, T. S.; Ding, H. X.; Khairul Anuar, A. N.; Ramli, N.; Sarmiento, I. J. K.; Perinan, M. T.; Fang, Z.-H.; Lange, L. M.; Kumar, K. R.; Bardien, S.; Trinh, J.; Valente, E. M.; SG10K_Health Consortium, ; Global Parkinson's Genetics Program (GP2), ; Heutink, P.; Lohmann, K.; Klein, C.; Mencacci, N. E.; Lim, S.-Y.; Ahmad-Annuar, A.; Tan, A. H.
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Introduction: GCH1 has been implicated in Parkinson's disease (PD), but its risks variants and associations are not well defined. Objectives: 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). 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%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. Conclusions: The GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD.
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