University of Oulu

Billingsley, K. J., Barbosa, I. A., Bandrés-Ciga, S., Quinn, J. P., Bubb, V. J., … Koks, S. (2019). Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset. Npj Parkinson’s Disease, 5(1). https://doi.org/10.1038/s41531-019-0080-x

Mitochondria function associated genes contribute to Parkinson’s Disease risk and later age at onset

Saved in:
Author: Billingsley, Kimberley J.1,2; Barbosa, Ines A.3; Bandrés-Ciga, Sara2;
Organizations: 1 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
2Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA
3Department of Medical and Molecular Genetics, King’s College London School of Basic and Medical Biosciences, London, SE1 9RT, UK
4Clinical Genetics Unit, Guys and St. Thomas’ NHS Foundation Trust, London, SE1 9RT, UK
5Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, 30100, Murcia, Spain
6Department of Neurodegenerative Disease, UCL Institute of Neurology, 10-12 Russell Square House, London, UK
7Montreal Neurological Institute, McGill University, Montréal, QC, Canada
8Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada
9Department of Human Genetics, McGill University, Montréal, QC, Canada
10Data Tecnica International, Glen Echo, MD, 20812, USA
11The Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA, 6009, Australia
12Centre for Comparative Genomics, Murdoch University, Murdoch, 6150, Australia
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.2 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2019092629852
Language: English
Published: Springer Nature, 2019
Publish Date: 2019-09-26
Description:

Abstract

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD.

see all

Additional information

International Parkinson’s Disease Genomics Consortium (IPDGC)

Members

A. Noyce13, A. Tucci14, B. Middlehurst1, D. Kia15, M. Tan16, H. Houlden14, H. R. Morris16, H. Plun-Favreau14, P. Holmans17, J. Hardy14, D. Trabzuni14,18, J. Bras19, K. Mok14, K. Kinghorn20, N. Wood15, P. Lewis21, R. Guerreiro14,19, R. Lovering22, L. R’Bibo14, M. Rizig14, V. Escott-Price22,23, V. Chelban14, T. Foltynie6, N. Williams24, A. Brice25, F. Danjou25, S. Lesage25, M. Martinez26, A. Giri27,28, C. Schulte27,28, K. Brockmann27,28, J. Simón-Sánchez27,28, P. Heutink27,28, P. Rizzu28, M. Sharma29, T. Gasser27,28, A. Nicolas2, M. Cookson2, F. Faghri2,30, D. Hernandez2, J. Shulman31,32, L. Robak33, S. Lubbe34, S. Finkbeiner35,36,37, N. Mencacci38, C. Lungu39, S. Scholz40, X. Reed2, H. Leonard2, G. Rouleau7, L. Krohan41, J. van Hilten42, J. Marinus42, A. Adarmes-Gómez43, M. Aguilar44, I. Alvarez44, V. Alvarez45, F. Javier Barrero46, J. Bergareche Yarza47, I. Bernal-Bernal43, M. Blazquez45, M. Bonilla-Toribio Bernal43, M. Boungiorno44, Dolores Buiza-Rueda43, A. Cámara48, M. Carcel44, F. Carrillo43, M. Carrión-Claro43, D. Cerdan49, J. Clarimón50,51, Y. Compta48, M. Diez-Fairen44, O. Dols-Icardo50,51, J. Duarte49, R. l. Duran52, F. Escamilla-Sevilla53, M. Ezquerra48, M. Fernández48, R. Fernández-Santiago48, C. Garcia45, P. García-Ruiz54, P. Gómez-Garre43, M. Gomez Heredia55, I. Gonzalez-Aramburu56, A. Gorostidi Pagola57, J. Hoenicka58, J. Infante51,56, S. Jesús43, A. Jimenez-Escrig59, J. Kulisevsky51,60, M. Labrador-Espinosa43, J. Lopez-Sendon59, A. López de Munain Arregui59, D. Macias43, I. Martínez Torres61, J. Marín51,60, M. Jose Marti48, J. Martínez-Castrillo59, C. Méndez-del-Barrio43, M. Menéndez González43, A. Mínguez53, P. Mir43, E. Mondragon Rezola57, E. Muñoz48, J. Pagonabarraga51,60, P. Pastor44, F. Perez Errazquin55, T. Periñán-Tocino43, J. Ruiz-Martínez57, C. Ruz52, A. Sanchez Rodriguez56, M. Sierra56, E. Suarez-Sanmartin4, C. Tabernero59, J. Pablo Tartari44, C. Tejera-Parrado43, E. Tolosa48, F. Valldeoriola48, L. Vargas-González43, L. Vela62, F. Vives52, A. Zimprich63, L. Pihlstrom64, P. Taba65, K. Majamaa66,67, A. Siitonen66, N. Okubadejo68, O. Ojo68

1 Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

2Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA

3Department of Medical and Molecular Genetics, King’s College London School of Basic and Medical Biosciences, London, SE1 9RT, UK

4Clinical Genetics Unit, Guys and St. Thomas’ NHS Foundation Trust, London, SE1 9RT, UK

5Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, 30100, Murcia, Spain

6Department of Neurodegenerative Disease, UCL Institute of Neurology, 10-12 Russell Square House, London, UK

7Montreal Neurological Institute, McGill University, Montréal, QC, Canada

8Department of Neurology and Neurosurgery, McGill University, Montréal, QC, Canada

9Department of Human Genetics, McGill University, Montréal, QC, Canada

10Data Tecnica International, Glen Echo, MD, 20812, USA

11The Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA, 6009, Australia

12Centre for Comparative Genomics, Murdoch University, Murdoch, 6150, Australia

13Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, QMUL, London, UK

14Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

15UCL Genetics Institute; and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

16Department of Clinical Neuroscience, University College London, London, UK

17Biostatistics & Bioinformatics Unit, Institute of Psychological Medicine and Clinical Neuroscience, MRC Centre for Neuropsychiatric Genetics & Genomics, Cardiff, UK

18Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia

19UK Dementia Research Institute at UCL and Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK

20Institute of Healthy Ageing, University College London, London, UK

21University of Reading, Reading, UK

22University College London, London, UK

23MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff, UK

24Cardiff University School of Medicine, Cardiff, UK

25Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06, UMR S 1127, AP-HP, Pitié-Salpêtrière Hospital, Paris, France

26INSERM UMR 1220; and Paul Sabatier University, Toulouse, France

27Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

28DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany

29Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Tubingen, Germany

30Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL, USA

31Departments of Neurology, Neuroscience, and Molecular & Human Genetics, Baylor College of Medicine, Houston, TX, USA

32Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, USA

33Baylor College of Medicine, Houston, TX, USA

34Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

35Departments of Neurology and Physiology, University of California, San Francisco, CA, USA

36Gladstone Institute of Neurological Disease, San Francisco, CA, USA

37Taube/Koret Center for Neurodegenerative Disease Research, San Francisco, CA, USA)

38 (Northwestern University Feinberg School of Medicine, Chicago, IL, USA)

39 (National Institutes of Health Division of Clinical Research, NINDS, National Institutes of Health, Bethesda, MD, USA)

40Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA

41Department of Human Genetics, McGill University, Montréal, QC H3A 0G4, Canada

42Department of Neurology, Leiden University Medical Center, Leiden, Netherlands

43Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, Seville, Spain

44Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain

45Hospital Universitario Central de Asturias, Oviedo, Spain

46Hospital Universitario Parque Tecnologico de la Salud, Granada, Spain

47Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain

48Hospital Clinic de Barcelona, Barcelona, Spain

49Hospital General de Segovia, Segovia, Spain

50Memory Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

51Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

52Centro de Investigacion Biomedica, Universidad de Granada, Granada, Spain

53Hospital Universitario Virgen de las Nieves, Instituto de Investigación Biosanitaria de Granada, Granada, Spain

54Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain

55Hospital Universitario Virgen de la Victoria, Malaga, Spain

56Hospital Universitario Marqués de Valdecilla-IDIVAL, Santander, Spain

57Instituto de Investigación Sanitaria Biodonostia, San Sebastián, Spain

58Institut de Recerca Sant Joan de Déu, Barcelona, Spain

59Hospital Universitario Ramón y Cajal Madrid, Madrid, Spain

60Movement Disorders Unit, Department of Neurology, IIB Sant Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain

61Department of Neurology, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain

62Department of Neurology, Hospital Universitario Fundación Alcorcón, Madrid, Spain

63Department of Neurology, Medical University of Vienna, Vienna, Austria

64Department of Neurology, Oslo University Hospital, Oslo, Norway

65Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia

66Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland

67Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland

68University of Lagos, Yaba, Lagos State, Nigeria

see all

Series: npj Parkinson's disease
ISSN: 2373-8057
ISSN-E: 2373-8057
ISSN-L: 2373-8057
Volume: 5
Article number: 8
DOI: 10.1038/s41531-019-0080-x
OADOI: https://oadoi.org/10.1038/s41531-019-0080-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
3112 Neurosciences
3111 Biomedicine
Subjects:
Funding: This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949.
Copyright information: © The Author(s) 2019. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  https://creativecommons.org/licenses/by/4.0/