Mitochondrial haplogroups and cognitive progression in Parkinson’s disease

Author:

Liu Ganqiang1ORCID,Ni Chunming1,Zhan Jiamin1,Li Weimin1,Luo Junfeng1,Liao Zhixiang23,Locascio Joseph J234,Xian Wenbiao5,Chen Ling5,Pei Zhong5ORCID,Corvol Jean-Christophe6,Maple-Grødem Jodi78,Campbell Meghan C9,Elbaz Alexis10ORCID,Lesage Suzanne6,Brice Alexis6,Hung Albert Y4,Schwarzschild Michael A4,Hayes Michael T11,Wills Anne-Marie4,Ravina Bernard12,Shoulson Ira13,Taba Pille1415,Kõks Sulev1617,Beach Thomas G18,Cormier-Dequaire Florence6,Alves Guido7819,Tysnes Ole-Bjørn2021,Perlmutter Joel S92223,Heutink Peter24,van Hilten Jacobus J25,Barker Roger A2627,Williams-Gray Caroline H26,Scherzer Clemens R23411,Liu Ganqiang,Valentino Rebecca R,Peng Jiajie,Liao Zhixiang,Locascio Joseph J,Corvol Jean-Christophe,Dong Xianjun,Maple-Grødem Jodi,Campbell Meghan C,Elbaz Alexis,Lesage Suzanne,Brice Alexis,Mangone Graziella,Growdon John H,Hung Albert Y,Schwarzchild Michael A,Hayes Michael T,Wills Anne-Marie,Herrington Todd M,Ravian Bernard,Shoulson Ira,Taba Pille,Kõks Sulev,Beach Thomas G,Cormier-Dequaire Florence,Alves Guido,Tysnes Ole-Bjørn,Perlmutter Joel S,Heutink Peter,van Hilten Jacobus J,Kasten Meike,Mollenhauer Brit,Trenkwalder Claudia,Klein Christine,Barker Roger A,Williams-Gray Caroline H,Marinus Johan,Scherzer Clemens R,

Affiliation:

1. Neurobiology Research Center, School of Medicine, Shenzhen Campus of Sun Yat-sen University , Shenzhen, Guangdong 518107 , China

2. APDA Center for Advanced Parkinson Research, Brigham and Women’s Hospital and Harvard Medical School , Boston, MA 02115 , USA

3. Neurogenomics Lab, Harvard Medical School, Brigham and Women's Hospital , Boston, MA 02115 , USA

4. Department of Neurology, Massachusetts General Hospital and Harvard Medical School , Boston, MA 02114 , USA

5. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, Guangdong 510080 , China

6. 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 , F-75013 Paris , France

7. The Norwegian Centre for Movement Disorders, Stavanger University Hospital , 4068 Stavanger , Norway

8. Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger , 4021 Stavanger , Norway

9. Department of Neurology, Washington University School of Medicine , St. Louis, MO 63110 , USA

10. Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, ‘Exposome and Heredity’ Team, CESP , F94805 Villejuif , France

11. Department of Neurology, Brigham and Women’s Hospital , Boston, MA 02115 , USA

12. Praxis Precision Medicines , Cambridge, MA 02142 , USA

13. Department of Neurology, Center for Health and Technology, University of Rochester , Rochester, NY 14642 , USA

14. Department of Neurology and Neurosurgery, Institute of Clinical Medicine, University of Tartu , Tartu 50406 , Estonia

15. Neurology Clinic, Tartu University Hospital , Tartu 50406 , Estonia

16. Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch , Perth, WA 6150 , Australia

17. Perron Institute for Neurological and Translational Science , Nedlands, WA 6009 , Australia

18. Banner Sun Health Research Institute , Sun City, AZ 85351 , USA

19. Department of Neurology, Stavanger University Hospital , 4068 Stavanger , Norway

20. Department of Neurology, Haukeland University Hospital , 5020 Bergen , Norway

21. Department of Clinical Medicine, University of Bergen , 5020 Bergen , Norway

22. Departments of Radiology and Neuroscience, Washington University School of Medicine , St. Louis, MO 63110 , USA

23. Program of Physical Therapy and Program of Occupational Therapy, Washington University School of Medicine , St. Louis, MO 63110 , USA

24. German Center for Neurodegenerative diseases (DZNE) , 72076 Tübingen , Germany

25. Department of Neurology, Leiden University Medical Center , 2333 ZA Leiden , The Netherlands

26. John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge , Cambridge CB2 0PY , UK

27. Wellcome—MRC Cambridge Stem Cell Institute, University of Cambridge , Cambridge CB2 0AW , UK

Abstract

Abstract Mitochondria are a culprit in the onset of Parkinson’s disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson’s disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10−6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56–0.81) and P = 2.46 × 10−5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson’s disease over time.

Funder

Fundamental Research Funds

Central Universities

Sun Yat-sen University

National Natural Science Foundation of China

Guangdong Basic and Applied Basic Research Foundation

Shenzhen Fundamental Research Program

The Pearl River Talent Recruitment Program

NIH

NINDS

NIA

American Parkinson Disease Association Center for Advanced Parkinson Research

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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