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.

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. Trabzuni^14,18, J. Bras¹⁹, K. Mok¹⁴, K. Kinghorn²⁰, N. Wood¹⁵, P. Lewis²¹, R. Guerreiro^14,19, R. Lovering²², L. R’Bibo¹⁴, M. Rizig¹⁴, V. Escott-Price^22,23, V. Chelban¹⁴, T. Foltynie⁶, N. Williams²⁴, A. Brice²⁵, F. Danjou²⁵, S. Lesage²⁵, M. Martinez²⁶, A. Giri^27,28, C. Schulte^27,28, K. Brockmann^27,28, J. Simón-Sánchez^27,28, P. Heutink^27,28, P. Rizzu²⁸, M. Sharma²⁹, T. Gasser^27,28, A. Nicolas², M. Cookson², F. Faghri^2,30, D. Hernandez², J. Shulman^31,32, L. Robak³³, S. Lubbe³⁴, S. Finkbeiner^35,36,37, 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. Clarimón^50,51, Y. Compta⁴⁸, M. Diez-Fairen⁴⁴, O. Dols-Icardo^50,51, 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. Infante^51,56, S. Jesús⁴³, A. Jimenez-Escrig⁵⁹, J. Kulisevsky^51,60, M. Labrador-Espinosa⁴³, J. Lopez-Sendon⁵⁹, A. López de Munain Arregui⁵⁹, D. Macias⁴³, I. Martínez Torres⁶¹, J. Marín^51,60, M. Jose Marti⁴⁸, J. Martínez-Castrillo⁵⁹, C. Méndez-del-Barrio⁴³, M. Menéndez González⁴³, A. Mínguez⁵³, P. Mir⁴³, E. Mondragon Rezola⁵⁷, E. Muñoz⁴⁸, J. Pagonabarraga^51,60, 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. Majamaa^66,67, 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