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

Tay YW 1 , Lee AL 2 , Schee JP 2 , Lin CH 3 , Tan EK 4 , Shin JH 5 Show all authors , Chen PS 6 , Fan SP 3 , Li CH 3 , Ng EYL 7 , Kim HJ 5 , Jeon B 5 , Koks S 8 , Vu HTT 9 , Mok KY 10 , Lim YT 11 , Kamaruddin MS 11 , Toh TS 2 , Ding HX 12 , Anuar ANK 2 , Ramli N 13 , Keller Sarmiento IJ 14 , Periñan MT 15 , Fang ZH 16 , Lange LM 17 , Kumar KR 18 , Bardien S 19 , Trinh J 20 , Valente EM 21 , SG10K_Health Consortium, the Global Parkinson's Genetics Program (GP2) , Heutink P 20 , Lohmann K 20 , Klein C 20 , Mencacci NE 14 , Lim SY 2 , Ahmad-Annuar A 1 , Tan AH 2

Affiliations 

  • 1 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 2 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 3 Department of Neurology, National Taiwan University Hospital Taipei, Taipei, Taiwan
  • 4 Duke-National University of Singapore Medical School, Singapore
  • 5 Department of Neurology, Seoul National University Hospital, College of Medicine, Seoul National University, Seoul, Republic of Korea
  • 6 Department of Neurology, National Taiwan University Hospital Bei-Hu branch, Taipei, Taiwan
  • 7 Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore
  • 8 Personalised Medicine Centre, Health Futures Institute, Murdoch University, Perth, Australia
  • 9 Scientific Research Department, National Geriatric Hospital, Hanoi, Vietnam
  • 10 The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, China
  • 11 Department of Biomedical Imaging, Universiti Malaya Research Imaging Centre, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 12 Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 13 Department of Radiology, Subang Jaya Medical Centre, Selangor, Malaysia
  • 14 Ken and Ruth Davee Department of Neurology and Simpson Querrey Center for Neurogenetics, Northwestern University, Feinberg School of Medicine, Chicago, Illnois, USA
  • 15 Centre for Preventive Neurology, Wolfson Institute of Population Health, Queen Mary University of London, London, United Kingdom
  • 16 DataTecnica, Washington, DC, USA
  • 17 Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
  • 18 Translational Neurogenomics Group, ANZAC Research Institute, Sydney Local Health District and Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
  • 19 Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
  • 20 Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
  • 21 Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy
Mov Disord, 2026 Oct 14.
PMID: 42876073 DOI: 10.1002/mds.70530

Abstract

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 = 22,372PD 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.

CONCLUSIONS: The GCH1 p.Ser80Asn variant is a rare, EAS-enriched risk variant for PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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