Genetic Analysis of the X Chromosome Associates Loci with Progression of Parkinson's Disease

Yu Liao^{1

2}, Hao Wu^{1

2}, Junhao Wang^{1

2}, Jean-Christophe Corvol³, Jodi Maple-Grødem^{4

5}, Meghan C Campbell⁶, Alexis Elbaz⁷, Alexis Brice³, Michael A Schwarzschild⁸, Pille Taba^{9

10}, Sulev Kõks^{11

12}, Thomas G Beach¹³, Guido Alves^{4

5

14}, Ole-Bjørn Tysnes^{15

16}, Joel S Perlmutter^{6

17

18}, Baijayanta Maiti⁶, Jacobus J van Hilten¹⁹, Roger A Barker^{20

21}, Caroline H Williams-Gray²⁰, Clemens R Scherzer^{22

23

24

25}, Ganqiang Liu^{1

2

26}; International Genetics of Parkinson Disease Progression Consortium

Affiliations

¹ Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China.
² Department of Medical Informatics and Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, Guangdong, China.
³ Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
⁴ The Centre for Movement Disorders, Centre for Brain Health, Stavanger University Hospital, Stavanger, Norway.
⁵ Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.
⁶ Department of Neurology and Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, France.
⁸ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹ Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹⁰ Neurology Clinic, Tartu University Hospital, Tartu, Estonia.
¹¹ Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia.
¹² Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
¹³ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁴ Department of Neurology, Stavanger University Hospital, Stavanger, Norway.
¹⁵ Department of Neurology, Haukeland University Hospital, Bergen, Norway.
¹⁶ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹⁷ Department of Radiology and Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁸ Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁹ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
²⁰ John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
²¹ Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
²² Stephen & Denise Adams Center for Parkinson's Disease Research, Yale School of Medicine, New Haven, Connecticut, USA.
²³ APDA Center for Parkinson Precision Medicine, Yale, New Haven, Connecticut, USA.
²⁴ Department of Neurology, Yale, New Haven, Connecticut, USA.
²⁵ Department of Genetics, Yale, New Haven, Connecticut, USA.
²⁶ Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China.

PMID: 40459076
PMCID: PMC12353966 (available on 2026-06-03)
DOI: 10.1002/mds.30252

Genetic Analysis of the X Chromosome Associates Loci with Progression of Parkinson's Disease

Yu Liao et al. Mov Disord. 2025 Sep.

. 2025 Sep;40(9):1908-1918.

doi: 10.1002/mds.30252. Epub 2025 Jun 3.

Authors

Affiliations

¹ Shenzhen Key Laboratory of Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen, Guangdong, China.
² Department of Medical Informatics and Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Shenzhen, Guangdong, China.
³ Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Assistance Publique Hôpitaux de Paris, Département de Neurologie et de Génétique, Hôpital Pitié-Salpêtrière, Paris, France.
⁴ The Centre for Movement Disorders, Centre for Brain Health, Stavanger University Hospital, Stavanger, Norway.
⁵ Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.
⁶ Department of Neurology and Radiology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁷ Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, France.
⁸ Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹ Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
¹⁰ Neurology Clinic, Tartu University Hospital, Tartu, Estonia.
¹¹ Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Perth, WA, Australia.
¹² Perron Institute for Neurological and Translational Science, Nedlands, WA, Australia.
¹³ Banner Sun Health Research Institute, Sun City, Arizona, USA.
¹⁴ Department of Neurology, Stavanger University Hospital, Stavanger, Norway.
¹⁵ Department of Neurology, Haukeland University Hospital, Bergen, Norway.
¹⁶ Department of Clinical Medicine, University of Bergen, Bergen, Norway.
¹⁷ Department of Radiology and Neuroscience, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁸ Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine, St. Louis, Missouri, USA.
¹⁹ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
²⁰ John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom.
²¹ Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom.
²² Stephen & Denise Adams Center for Parkinson's Disease Research, Yale School of Medicine, New Haven, Connecticut, USA.
²³ APDA Center for Parkinson Precision Medicine, Yale, New Haven, Connecticut, USA.
²⁴ Department of Neurology, Yale, New Haven, Connecticut, USA.
²⁵ Department of Genetics, Yale, New Haven, Connecticut, USA.
²⁶ Guangdong Provincial Key Laboratory of Brain Function and Disease, Guangzhou, Guangdong, China.

PMID: 40459076
PMCID: PMC12353966 (available on 2026-06-03)
DOI: 10.1002/mds.30252

Abstract

Background: Genetic variants on the X chromosome have been linked to susceptibility for Parkinson's disease (PD), but their roles in disease progression remain unclear.

Objectives: This study investigated associations between X chromosome variants and longitudinal cognitive decline or motor impairment in patients with PD.

Methods: We conducted combined (male + female) and stratified X-chromosome-wide survival studies (XWSS) in 4467 patients with PD with 33,406 longitudinal visits. Cognitive decline was defined as global cognitive impairment (GCI, Mini Mental State Exam score ≤25), whereas motor impairment was evaluated by Hoehn and Yahr stage 3 (HY3). Expression quantitative trait locus (eQTL) and genetic colocalization analyses were systematically performed.

Results: We identified 40 common variants in the X-chromosome-wide screen associated with longitudinal progression of PD with P-value <9.27 × 10^-6, including 11 independent loci associated with cognitive decline and two with motor impairment. The rs142724191 and rs144112368 variants were associated with cognitive decline in both combined and male-only analyses. rs111708875 reached genome-wide significance for motor progression in female cases (hazard ratio [HR] = 3.98, 95% confidence interval [CI]: 2.54-6.25) with P-value = 1.84 × 10^-9. All these variants were independent with X chromosome susceptibility loci associated with PD, Alzheimer's disease, or Lewy body dementia.

Conclusions: Our XWSS identified novel genetic progression-associated loci on the X chromosome for PD, providing new insights into the X chromosome-linked genetic underpinnings of PD. © 2025 International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; X‐chromosome‐wide survival study; eQTL; progression.

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Conflict of interest statement

Conflict of Interest:

All authors report no competing interests.

References

1. Aarsland D, Batzu L, Halliday GM, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers 2021;7:47. - PubMed
1. Dorsey ER, Sherer T, Okun MS, Bloem BR. The Emerging Evidence of the Parkinson Pandemic. J Parkinsons Dis 2018;8:S3–S8. - PMC - PubMed
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1. Zirra A, Rao SC, Bestwick J, et al. Gender Differences in the Prevalence of Parkinson’s Disease. Mov Disord Clin Pract 2023;10:86–93. - PMC - PubMed
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Genetic Analysis of the X Chromosome Associates Loci with Progression of Parkinson's Disease

Affiliations

Genetic Analysis of the X Chromosome Associates Loci with Progression of Parkinson's Disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical