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

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 = 22,372 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. © 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.

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Journal
Movement Disorders
Published
2026-10-14
DOI
https://doi.org/10.1002/mds.70530
Primary Topic
Parkinson's Disease Mechanisms and Treatments
Type
article
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article

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

Pin‐Shiuan Chen, Katja Lohmann, Joanne Trinh, Zih‐Hua Fang et al.
Movement Disorders
Parkinson's Disease Mechanisms and Treatments
article

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

Pin‐Shiuan Chen, Katja Lohmann, Joanne Trinh, Zih‐Hua Fang, Christine Klein, Huyen Thi Thanh Vu, Norlisah Mohd Ramli, Ebonne Yu Lin Ng, Chin‐Hsien Lin, Sulev Kõks, Tzi Shin Toh, Lara Mariah Lange, Niccolò Emanuele Mencacci, Shen‐Yang Lim, Soraya Bardien, Beomseok Jeon, Peter Heutink, Yi Wen Tay, Enza Maria Valente, Ai Huey Tan, Yi Ting Lim, Ignacio Juan Keller Sarmiento, Sung‐Pin Fan, Jung Hwan Shin, Jie Ping Schee, Eng‐King Tan, Han‐Joon Kim, Kishore Raj Kumar, María Teresa Periñán, Kin Ying Mok, Azlina Ahmad‐Annuar, Cheng‐Hsuan Li, Andrew Leslie Lee, Anis Nadhirah Khairul Anuar, Mohd Salahuddin Bin Kamaruddin, Hans Xing Ding
article en

Abstract

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 = 22,372 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. © 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.

Movement Disorders
South African Medical Research Council (ZA), Northwestern University (US), University Malaya Medical Centre (MY), National Institutes of Health (US), Garvan Institute of Medical Research (AU), National University of Singapore (SG), Queen Mary University of London (GB), Murdoch University (AU), Hanoi Medical University (VN), Hong Kong University of Science and Technology (HK), Singapore General Hospital (SG), University of Pavia (IT), Stellenbosch University (ZA), Hong Kong Science and Technology Parks Corporation (HK), Seoul National University Hospital (KR), UNSW Sydney (AU), University of Malaya (MY), Data Tecnica International (United States) (US), Fondazione Istituto Neurologico Nazionale Casimiro Mondino (IT), Duke-NUS Medical School (SG), National Neuroscience Institute (SG), National Taiwan University Hospital (TW), National Institute on Aging (US), Sydney Local Health District (AU), Perron Institute for Neurological and Translational Science (AU), Subang Jaya Medical Centre (MY), Anzac Research Institute (AU), Hospital Universitario Virgen del Rocío (ES), University of Hong Kong (HK), University of Lübeck (DE)
Openalex Percentile: Top 14%
Parkinson's Disease Mechanisms and Treatments
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