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

doi:10.1038/s41531-019-0080-x

. 2019 May 22:5:8.

doi: 10.1038/s41531-019-0080-x. eCollection 2019.

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

Kimberley J Billingsley^#^{1

2}, Ines A Barbosa^#³, Sara Bandrés-Ciga², John P Quinn¹, Vivien J Bubb¹, Charu Deshpande⁴, Juan A Botia^{5

6}, Regina H Reynolds⁶, David Zhang⁶, Michael A Simpson³, Cornelis Blauwendraat², Ziv Gan-Or^{7

8

9}, J Raphael Gibbs², Mike A Nalls^{2

10}, Andrew Singleton²; International Parkinson’s Disease Genomics Consortium (IPDGC); Mina Ryten^#⁶, Sulev Koks^#^{11

12}

Collaborators, Affiliations

Collaborators

International Parkinson’s Disease Genomics Consortium (IPDGC):
A Noyce, A Tucci, B Middlehurst, D Kia, M Tan, H Houlden, H R Morris, H Plun-Favreau, P Holmans, J Hardy, D Trabzuni, J Bras, K Mok, K Kinghorn, N Wood, P Lewis, R Guerreiro, R Lovering, L R'Bibo, M Rizig, V Escott-Price, V Chelban, T Foltynie, N Williams, A Brice, F Danjou, S Lesage, M Martinez, A Giri, C Schulte, K Brockmann, J Simón-Sánchez, P Heutink, P Rizzu, M Sharma, T Gasser, A Nicolas, M Cookson, F Faghri, D Hernandez, J Shulman, L Robak, S Lubbe, S Finkbeiner, N Mencacci, C Lungu, S Scholz, X Reed, H Leonard, G Rouleau, L Krohan, J van Hilten, J Marinus, A Adarmes-Gómez, M Aguilar, I Alvarez, V Alvarez, F Javier Barrero, J Bergareche Yarza, I Bernal-Bernal, M Blazquez, M Bonilla-Toribio Bernal, M Boungiorno, Dolores Buiza-Rueda, A Cámara, M Carcel, F Carrillo, M Carrión-Claro, D Cerdan, J Clarimón, Y Compta, M Diez-Fairen, O Dols-Icardo, J Duarte, R L Duran, F Escamilla-Sevilla, M Ezquerra, M Fernández, R Fernández-Santiago, C Garcia, P García-Ruiz, P Gómez-Garre, M Gomez Heredia, I Gonzalez-Aramburu, A Gorostidi Pagola, J Hoenicka, J Infante, S Jesús, A Jimenez-Escrig, J Kulisevsky, M Labrador-Espinosa, J Lopez-Sendon, A López de Munain Arregui, D Macias, I Martínez Torres, J Marín, M Jose Marti, J Martínez-Castrillo, C Méndez-Del-Barrio, M Menéndez González, A Mínguez, P Mir, E Mondragon Rezola, E Muñoz, J Pagonabarraga, P Pastor, F Perez Errazquin, T Periñán-Tocino, J Ruiz-Martínez, C Ruz, A Sanchez Rodriguez, M Sierra, E Suarez-Sanmartin, C Tabernero, J Pablo Tartari, C Tejera-Parrado, E Tolosa, F Valldeoriola, L Vargas-González, L Vela, F Vives, A Zimprich, L Pihlstrom, P Taba, K Majamaa, A Siitonen, N Okubadejo, O Ojo

Affiliations

¹ 1Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, , University of Liverpool, Liverpool, UK.
² 2Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892 USA.
³ 3Department of Medical and Molecular Genetics, King's College London School of Basic and Medical Biosciences, London, SE1 9RT UK.
⁴ 4Clinical Genetics Unit, Guys and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK.
⁵ 5Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, 30100 Murcia, Spain.
⁶ 6Department of Neurodegenerative Disease, UCL Institute of Neurology, 10-12 Russell Square House, London, UK.
⁷ 7Montreal Neurological Institute, McGill University, Montréal, QC Canada.
⁸ 8Department of Neurology and Neurosurgery, McGill University, Montréal, QC Canada.
⁹ 9Department of Human Genetics, McGill University, Montréal, QC Canada.
¹⁰ Data Tecnica International, Glen Echo, MD 20812 USA.
¹¹ 11The Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA 6009 Australia.
¹² 12Centre for Comparative Genomics, Murdoch University, Murdoch, 6150 Australia.

^# Contributed equally.

PMID: 31123700
PMCID: PMC6531455
DOI: 10.1038/s41531-019-0080-x

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

Kimberley J Billingsley et al. NPJ Parkinsons Dis. 2019.

. 2019 May 22:5:8.

doi: 10.1038/s41531-019-0080-x. eCollection 2019.

Authors

Collaborators

International Parkinson’s Disease Genomics Consortium (IPDGC):
A Noyce, A Tucci, B Middlehurst, D Kia, M Tan, H Houlden, H R Morris, H Plun-Favreau, P Holmans, J Hardy, D Trabzuni, J Bras, K Mok, K Kinghorn, N Wood, P Lewis, R Guerreiro, R Lovering, L R'Bibo, M Rizig, V Escott-Price, V Chelban, T Foltynie, N Williams, A Brice, F Danjou, S Lesage, M Martinez, A Giri, C Schulte, K Brockmann, J Simón-Sánchez, P Heutink, P Rizzu, M Sharma, T Gasser, A Nicolas, M Cookson, F Faghri, D Hernandez, J Shulman, L Robak, S Lubbe, S Finkbeiner, N Mencacci, C Lungu, S Scholz, X Reed, H Leonard, G Rouleau, L Krohan, J van Hilten, J Marinus, A Adarmes-Gómez, M Aguilar, I Alvarez, V Alvarez, F Javier Barrero, J Bergareche Yarza, I Bernal-Bernal, M Blazquez, M Bonilla-Toribio Bernal, M Boungiorno, Dolores Buiza-Rueda, A Cámara, M Carcel, F Carrillo, M Carrión-Claro, D Cerdan, J Clarimón, Y Compta, M Diez-Fairen, O Dols-Icardo, J Duarte, R L Duran, F Escamilla-Sevilla, M Ezquerra, M Fernández, R Fernández-Santiago, C Garcia, P García-Ruiz, P Gómez-Garre, M Gomez Heredia, I Gonzalez-Aramburu, A Gorostidi Pagola, J Hoenicka, J Infante, S Jesús, A Jimenez-Escrig, J Kulisevsky, M Labrador-Espinosa, J Lopez-Sendon, A López de Munain Arregui, D Macias, I Martínez Torres, J Marín, M Jose Marti, J Martínez-Castrillo, C Méndez-Del-Barrio, M Menéndez González, A Mínguez, P Mir, E Mondragon Rezola, E Muñoz, J Pagonabarraga, P Pastor, F Perez Errazquin, T Periñán-Tocino, J Ruiz-Martínez, C Ruz, A Sanchez Rodriguez, M Sierra, E Suarez-Sanmartin, C Tabernero, J Pablo Tartari, C Tejera-Parrado, E Tolosa, F Valldeoriola, L Vargas-González, L Vela, F Vives, A Zimprich, L Pihlstrom, P Taba, K Majamaa, A Siitonen, N Okubadejo, O Ojo

Affiliations

¹ 1Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, , University of Liverpool, Liverpool, UK.
² 2Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892 USA.
³ 3Department of Medical and Molecular Genetics, King's College London School of Basic and Medical Biosciences, London, SE1 9RT UK.
⁴ 4Clinical Genetics Unit, Guys and St. Thomas' NHS Foundation Trust, London, SE1 9RT UK.
⁵ 5Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, 30100 Murcia, Spain.
⁶ 6Department of Neurodegenerative Disease, UCL Institute of Neurology, 10-12 Russell Square House, London, UK.
⁷ 7Montreal Neurological Institute, McGill University, Montréal, QC Canada.
⁸ 8Department of Neurology and Neurosurgery, McGill University, Montréal, QC Canada.
⁹ 9Department of Human Genetics, McGill University, Montréal, QC Canada.
¹⁰ Data Tecnica International, Glen Echo, MD 20812 USA.
¹¹ 11The Perron Institute for Neurological and Translational Science, 8 Verdun Street, Nedlands, WA 6009 Australia.
¹² 12Centre for Comparative Genomics, Murdoch University, Murdoch, 6150 Australia.

^# Contributed equally.

PMID: 31123700
PMCID: PMC6531455
DOI: 10.1038/s41531-019-0080-x

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.

Keywords: Medical genetics; Risk factors.

PubMed Disclaimer

Conflict of interest statement

Competing interestsMike A. Nalls’ participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA, as a possible conflict of interest Dr. Nalls also consults for Neuro23 Inc, Lysosomal Therapeutics Inc, the Michael J. Fox Foundation, Illumina Inc. and Vivid Genomics among others. Dr. Gan-or also consults for for Lysosomal Therapeutics Inc., Denaly, Prevail Therapeutics, Idorsia, and Allergan. The other authors declare no competing interests.

Figures

**Fig. 1**
Workflow of mitochondrial-function specific PD analysis

**Fig. 2. Forest plots of PRS for Parkinson’s Disease across cohorts.**
Random effect meta-analysis results are shown as red diamonds and fixed effects are shown as blue, with the centerline of each diamond representing the summary PRS for that dataset. IPDGC NeuroX = (Nalls et al. 2015, PMID:25444595), OSLO = Oslo Parkinson’s Disease Study, PDBP = Parkinson’s Disease Biomarker’s Program, PPMI = Parkinson’s Progression Markers Initiative, Baylor = Baylor College of Medicine/University of Maryland, German GWAS = (PMID:19915575), VANCE = Vance (dbGap phs000394)

**Fig. 3. Forest plots of PRS for the age at onset of Parkinson’s Disease across cohorts.**
Random effect meta-analysis results are shown as red diamonds and fixed effects are shown as blue, with the centerline of each diamond representing the summary PRS for that dataset. OSLO = Oslo Parkinson’s Disease Study, PDBP = Parkinson’s Disease Biomarker’s Program, PPMI = Parkinson’s Progression Markers Initiative, German GWAS = (PMID:19915575), VANCE = Vance

See this image and copyright information in PMC

Cited by

Improved Parkinsons disease motor score in a single-arm open-label trial of febuxostat and inosine.
Watanabe H, Hattori T, Kume A, Misu K, Ito T, Koike Y, Johnson TA, Kamitsuji S, Kamatani N, Sobue G. Watanabe H, et al. Medicine (Baltimore). 2020 Aug 28;99(35):e21576. doi: 10.1097/MD.0000000000021576. Medicine (Baltimore). 2020. PMID: 32871874 Free PMC article. Clinical Trial.
The Quebec Parkinson Network: A Researcher-Patient Matching Platform and Multimodal Biorepository.
Gan-Or Z, Rao T, Leveille E, Degroot C, Chouinard S, Cicchetti F, Dagher A, Das S, Desautels A, Drouin-Ouellet J, Durcan T, Gagnon JF, Genge A, Karamchandani J, Lafontaine AL, Sun SLW, Langlois M, Levesque M, Melmed C, Panisset M, Parent M, Poline JB, Postuma RB, Pourcher E, Rouleau GA, Sharp M, Monchi O, Dupré N, Fon EA. Gan-Or Z, et al. J Parkinsons Dis. 2020;10(1):301-313. doi: 10.3233/JPD-191775. J Parkinsons Dis. 2020. PMID: 31868683 Free PMC article.
Ten Years of the International Parkinson Disease Genomics Consortium: Progress and Next Steps.
International Parkinson Disease Genomics Consortium (IPDGC). International Parkinson Disease Genomics Consortium (IPDGC). J Parkinsons Dis. 2020;10(1):19-30. doi: 10.3233/JPD-191854. J Parkinsons Dis. 2020. PMID: 31815703 Free PMC article.
Parkinson's disease therapy: what lies ahead?
Wolff A, Schumacher NU, Pürner D, Machetanz G, Demleitner AF, Feneberg E, Hagemeier M, Lingor P. Wolff A, et al. J Neural Transm (Vienna). 2023 Jun;130(6):793-820. doi: 10.1007/s00702-023-02641-6. Epub 2023 May 5. J Neural Transm (Vienna). 2023. PMID: 37147404 Free PMC article. Review.
Integrative single-cell analysis: dissecting CD8 + memory cell roles in LUAD and COVID-19 via eQTLs and Mendelian Randomization.
Wu J, Mao X, Liu X, Mao J, Yang X, Zhou X, Tianzhu L, Ji Y, Li Z, Xu H. Wu J, et al. Hereditas. 2024 Jan 31;161(1):7. doi: 10.1186/s41065-023-00307-7. Hereditas. 2024. PMID: 38297377 Free PMC article.

See all "Cited by" articles

References

1. Singleton A, Hardy J. The evolution of genetics: Alzheimer’s and Parkinson’s Diseases. Neuron. 2016;90:1154–1163. doi: 10.1016/j.neuron.2016.05.040. - DOI - PMC - PubMed
1. Gasser T. Genetics of parkinson’s disease. Ann. Neurol. 1998;44:S53–S57. doi: 10.1002/ana.410440708. - DOI - PubMed
1. Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res. Rev. 2014;14:19–30. doi: 10.1016/j.arr.2014.01.004. - DOI - PMC - PubMed
1. Chang D, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 2017;49:1511–1516. doi: 10.1038/ng.3955. - DOI - PMC - PubMed
1. Nalls MA, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 2014;46:989–993. doi: 10.1038/ng.3043. - DOI - PMC - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database

[1] Singleton A, Hardy J. The evolution of genetics: Alzheimer’s and Parkinson’s Diseases. Neuron. 2016;90:1154–1163. doi: 10.1016/j.neuron.2016.05.040. - DOI - PMC - PubMed

[2] Singleton A, Hardy J. The evolution of genetics: Alzheimer’s and Parkinson’s Diseases. Neuron. 2016;90:1154–1163. doi: 10.1016/j.neuron.2016.05.040. - DOI - PMC - PubMed

[3] Gasser T. Genetics of parkinson’s disease. Ann. Neurol. 1998;44:S53–S57. doi: 10.1002/ana.410440708. - DOI - PubMed

[4] Gasser T. Genetics of parkinson’s disease. Ann. Neurol. 1998;44:S53–S57. doi: 10.1002/ana.410440708. - DOI - PubMed

[5] Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res. Rev. 2014;14:19–30. doi: 10.1016/j.arr.2014.01.004. - DOI - PMC - PubMed

[6] Reeve A, Simcox E, Turnbull D. Ageing and Parkinson’s disease: why is advancing age the biggest risk factor? Ageing Res. Rev. 2014;14:19–30. doi: 10.1016/j.arr.2014.01.004. - DOI - PMC - PubMed

[7] Chang D, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 2017;49:1511–1516. doi: 10.1038/ng.3955. - DOI - PMC - PubMed

[8] Chang D, et al. A meta-analysis of genome-wide association studies identifies 17 new Parkinson’s disease risk loci. Nat. Genet. 2017;49:1511–1516. doi: 10.1038/ng.3955. - DOI - PMC - PubMed

[9] Nalls MA, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 2014;46:989–993. doi: 10.1038/ng.3043. - DOI - PMC - PubMed

[10] Nalls MA, et al. Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson’s disease. Nat. Genet. 2014;46:989–993. doi: 10.1038/ng.3043. - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

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

Collaborators

Affiliations

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

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources