Meta-Analysis

. 2019 Dec;18(12):1091-1102.

doi: 10.1016/S1474-4422(19)30320-5.

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Mike A Nalls¹, Cornelis Blauwendraat², Costanza L Vallerga³, Karl Heilbron⁴, Sara Bandres-Ciga², Diana Chang⁵, Manuela Tan⁶, Demis A Kia⁶, Alastair J Noyce⁷, Angli Xue⁸, Jose Bras⁹, Emily Young¹⁰, Rainer von Coelln¹¹, Javier Simón-Sánchez¹², Claudia Schulte¹², Manu Sharma¹³, Lynne Krohn¹⁴, Lasse Pihlstrøm¹⁵, Ari Siitonen¹⁶, Hirotaka Iwaki¹⁷, Hampton Leonard¹⁸, Faraz Faghri¹⁹, J Raphael Gibbs², Dena G Hernandez², Sonja W Scholz²⁰, Juan A Botia²¹, Maria Martinez²², Jean-Christophe Corvol²³, Suzanne Lesage²³, Joseph Jankovic¹⁰, Lisa M Shulman¹¹, Margaret Sutherland²⁴, Pentti Tienari²⁵, Kari Majamaa¹⁶, Mathias Toft²⁶, Ole A Andreassen²⁷, Tushar Bangale⁵, Alexis Brice²³, Jian Yang⁸, Ziv Gan-Or²⁸, Thomas Gasser¹², Peter Heutink¹², Joshua M Shulman²⁹, Nicholas W Wood⁶, David A Hinds⁴, John A Hardy³⁰, Huw R Morris³¹, Jacob Gratten³², Peter M Visscher⁸, Robert R Graham⁵, Andrew B Singleton²; 23andMe Research Team; System Genomics of Parkinson's Disease Consortium; International Parkinson's Disease Genomics Consortium

Collaborators, Affiliations

Collaborators

Astrid D Adarmes-Gómez, Miquel Aguilar, Akbota Aitkulova, Vadim Akhmetzhanov, Roy N Alcalay, Ignacio Alvarez, Victoria Alvarez, Sara Bandres-Ciga, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal-Bernal, Kimberley Billingsley, Cornelis Blauwendraat, Marta Blazquez, Marta Bonilla-Toribio, Juan A Botía, María Teresa Boungiorno, Jose Bras, Alexis Brice, Kathrin Brockmann, Vivien Bubb, Dolores Buiza-Rueda, Ana Cámara, Fátima Carrillo, Mario Carrión-Claro, Debora Cerdan, Viorica Chelban, Jordi Clarimón, Carl Clarke, Yaroslau Compta, Mark R Cookson, Jean-Christophe Corvol, David W Craig, Fabrice Danjou, Monica Diez-Fairen, Oriol Dols-Icardo, Jacinto Duarte, Raquel Duran, Francisco Escamilla-Sevilla, Valentina Escott-Price, Mario Ezquerra, Faraz Faghri, Cici Feliz, Manel Fernández, Rubén Fernández-Santiago, Steven Finkbeiner, Thomas Foltynie, Ziv Gan-Or, Ciara Garcia, Pedro García-Ruiz, Thomas Gasser, J Raphael Gibbs, Maria Jose Gomez Heredia, Pilar Gómez-Garre, Manuel Menéndez González, Isabel Gonzalez-Aramburu, Sebastian Guelfi, Rita Guerreiro, John Hardy, Sharon Hassin-Baer, Dena G Hernandez, Peter Heutink, Janet Hoenicka, Peter Holmans, Henry Houlden, Jon Infante, Hirotaka Iwaki, Silvia Jesús, Adriano Jimenez-Escrig, Gulnaz Kaishybayeva, Rauan Kaiyrzhanov, Altynay Karimova, Demis A Kia, Kerri J Kinghorn, Sulev Koks, Lynne Krohn, Jaime Kulisevsky, Miguel A Labrador-Espinosa, Hampton L Leonard, Suzanne Lesage, Patrick Lewis, Jose Luis Lopez-Sendon, Ruth Lovering, Steven Lubbe, Codrin Lungu, Daniel Macias, Kari Majamaa, Claudia Manzoni, Juan Marín, Johan Marinus, Maria Jose Marti, Maria Martinez, Irene Martínez Torres, Juan Carlos Martínez-Castrillo, Marina Mata, Niccolo E Mencacci, Carlota Méndez-Del-Barrio, Ben Middlehurst, Adolfo Mínguez, Pablo Mir, Kin Y Mok, Huw R Morris, Esteban Muñoz, Mike A Nalls, Derek Narendra, Alastair J Noyce, Oluwadamilola O Ojo, Njideka U Okubadejo, Ana Gorostidi Pagola, Pau Pastor, Francisco Perez Errazquin, Teresa Periñán-Tocino, Lasse Pihlstrom, Helene Plun-Favreau, John Quinn, Lea R'Bibo, Xylena Reed, Elisabet Mondragon Rezola, Mie Rizig, Patrizia Rizzu, Laurie Robak, Antonio Sanchez Rodriguez, Guy A Rouleau, Javier Ruiz-Martínez, Clara Ruz, Mina Ryten, Dinara Sadykova, Sonja W Scholz, Sebastian Schreglmann, Claudia Schulte, Manu Sharma, Chingiz Shashkin, Joshua M Shulman, María Sierra, Ari Siitonen, Javier Simón-Sánchez, Andrew B Singleton, Esther Suarez-Sanmartin, Pille Taba, Cesar Tabernero, Manuela X Tan, Juan Pablo Tartari, Cristina Tejera-Parrado, Mathias Toft, Eduard Tolosa, Daniah Trabzuni, Francesc Valldeoriola, Jacobus J van Hilten, Kendall Van Keuren-Jensen, Laura Vargas-González, Lydia Vela, Francisco Vives, Nigel Williams, Nicholas W Wood, Nazira Zharkinbekova, Zharkyn Zharmukhanov, Elena Zholdybayeva, Alexander Zimprich, Pauli Ylikotila, Lisa M Shulman, Rainer von Coelln, Stephen Reich, Joseph Savitt, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, Karen E Huber, Barry Hicks, Ethan M Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K Litterman, Jennifer C McCreight, Matthew H McIntyre, Kimberly F McManus, Joanna L Mountain, Elizabeth S Noblin, Carrie A M Northover, Steven J Pitts, G David Poznik, J Fah Sathirapongsasuti, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Tung, Vladimir Vacic, Xin Wang, Catherine H Wilson, Tim Anderson, Steven Bentley, John Dalrymple-Alford, Javed Fowdar, Jacob Gratten, Glenda Halliday, Anjali K Henders, Ian Hickie, Irfahan Kassam, Martin Kennedy, John Kwok, Simon Lewis, George Mellick, Grant Montgomery, John Pearson, Toni Pitcher, Julia Sidorenko, Peter A Silburn, Costanza L Vallerga, Peter M Visscher, Leanne Wallace, Naomi R Wray, Angli Xue, Jian Yang, Futao Zhang

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA. Electronic address: mike@datatecnica.com.
² Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁴ 23andMe, Sunnyvale, CA, USA.
⁵ Department of Human Genetics, Genentech, South San Francisco, CA, USA.
⁶ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK; Department of Clinical and Movement Neuroscience and UCL Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK.
⁷ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK; Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
⁸ Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁹ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK; Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
¹⁰ Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
¹¹ Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
¹² Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases, Tübingen, Germany.
¹³ Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
¹⁴ Department of Human Genetics, McGill University, Montreal, QC, Canada; Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
¹⁵ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁶ Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland; Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland.
¹⁷ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA; The Michael J Fox Foundation, New York, NY, USA.
¹⁸ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA.
¹⁹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Computer Science, University of Illinois Urbana-Champaign, Champaign, IL, USA.
²⁰ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
²¹ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK; Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Spain.
²² Institut national de la santé et de la recherche médicale Unité mixte de recherche 1220, Toulouse, France; Paul Sabatier University, Toulouse, France.
²³ Institut national de la santé et de la recherche médicale U1127, CNRS UMR 7225, Paris, France; Sorbonne Université centre national de la recherche médicale, unité mixte de recherche 1127, Paris, France; Assistance Publique Hôpitaux de Paris, Paris, France; Institut du Cerveau et de la Moelle épinière, Paris, France.
²⁴ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
²⁵ Clinical Neurosciences, Neurology, University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland.
²⁶ Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²⁷ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway.
²⁸ Department of Human Genetics, McGill University, Montreal, QC, Canada; Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
²⁹ Department of Neurology, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
³⁰ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK.
³¹ Department of Clinical and Movement Neuroscience and UCL Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK.
³² Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia; Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia.

PMID: 31701892
PMCID: PMC8422160
DOI: 10.1016/S1474-4422(19)30320-5

Meta-Analysis

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Mike A Nalls et al. Lancet Neurol. 2019 Dec.

. 2019 Dec;18(12):1091-1102.

doi: 10.1016/S1474-4422(19)30320-5.

Authors

Collaborators

Astrid D Adarmes-Gómez, Miquel Aguilar, Akbota Aitkulova, Vadim Akhmetzhanov, Roy N Alcalay, Ignacio Alvarez, Victoria Alvarez, Sara Bandres-Ciga, Francisco Javier Barrero, Jesús Alberto Bergareche Yarza, Inmaculada Bernal-Bernal, Kimberley Billingsley, Cornelis Blauwendraat, Marta Blazquez, Marta Bonilla-Toribio, Juan A Botía, María Teresa Boungiorno, Jose Bras, Alexis Brice, Kathrin Brockmann, Vivien Bubb, Dolores Buiza-Rueda, Ana Cámara, Fátima Carrillo, Mario Carrión-Claro, Debora Cerdan, Viorica Chelban, Jordi Clarimón, Carl Clarke, Yaroslau Compta, Mark R Cookson, Jean-Christophe Corvol, David W Craig, Fabrice Danjou, Monica Diez-Fairen, Oriol Dols-Icardo, Jacinto Duarte, Raquel Duran, Francisco Escamilla-Sevilla, Valentina Escott-Price, Mario Ezquerra, Faraz Faghri, Cici Feliz, Manel Fernández, Rubén Fernández-Santiago, Steven Finkbeiner, Thomas Foltynie, Ziv Gan-Or, Ciara Garcia, Pedro García-Ruiz, Thomas Gasser, J Raphael Gibbs, Maria Jose Gomez Heredia, Pilar Gómez-Garre, Manuel Menéndez González, Isabel Gonzalez-Aramburu, Sebastian Guelfi, Rita Guerreiro, John Hardy, Sharon Hassin-Baer, Dena G Hernandez, Peter Heutink, Janet Hoenicka, Peter Holmans, Henry Houlden, Jon Infante, Hirotaka Iwaki, Silvia Jesús, Adriano Jimenez-Escrig, Gulnaz Kaishybayeva, Rauan Kaiyrzhanov, Altynay Karimova, Demis A Kia, Kerri J Kinghorn, Sulev Koks, Lynne Krohn, Jaime Kulisevsky, Miguel A Labrador-Espinosa, Hampton L Leonard, Suzanne Lesage, Patrick Lewis, Jose Luis Lopez-Sendon, Ruth Lovering, Steven Lubbe, Codrin Lungu, Daniel Macias, Kari Majamaa, Claudia Manzoni, Juan Marín, Johan Marinus, Maria Jose Marti, Maria Martinez, Irene Martínez Torres, Juan Carlos Martínez-Castrillo, Marina Mata, Niccolo E Mencacci, Carlota Méndez-Del-Barrio, Ben Middlehurst, Adolfo Mínguez, Pablo Mir, Kin Y Mok, Huw R Morris, Esteban Muñoz, Mike A Nalls, Derek Narendra, Alastair J Noyce, Oluwadamilola O Ojo, Njideka U Okubadejo, Ana Gorostidi Pagola, Pau Pastor, Francisco Perez Errazquin, Teresa Periñán-Tocino, Lasse Pihlstrom, Helene Plun-Favreau, John Quinn, Lea R'Bibo, Xylena Reed, Elisabet Mondragon Rezola, Mie Rizig, Patrizia Rizzu, Laurie Robak, Antonio Sanchez Rodriguez, Guy A Rouleau, Javier Ruiz-Martínez, Clara Ruz, Mina Ryten, Dinara Sadykova, Sonja W Scholz, Sebastian Schreglmann, Claudia Schulte, Manu Sharma, Chingiz Shashkin, Joshua M Shulman, María Sierra, Ari Siitonen, Javier Simón-Sánchez, Andrew B Singleton, Esther Suarez-Sanmartin, Pille Taba, Cesar Tabernero, Manuela X Tan, Juan Pablo Tartari, Cristina Tejera-Parrado, Mathias Toft, Eduard Tolosa, Daniah Trabzuni, Francesc Valldeoriola, Jacobus J van Hilten, Kendall Van Keuren-Jensen, Laura Vargas-González, Lydia Vela, Francisco Vives, Nigel Williams, Nicholas W Wood, Nazira Zharkinbekova, Zharkyn Zharmukhanov, Elena Zholdybayeva, Alexander Zimprich, Pauli Ylikotila, Lisa M Shulman, Rainer von Coelln, Stephen Reich, Joseph Savitt, Michelle Agee, Babak Alipanahi, Adam Auton, Robert K Bell, Katarzyna Bryc, Sarah L Elson, Pierre Fontanillas, Nicholas A Furlotte, Karen E Huber, Barry Hicks, Ethan M Jewett, Yunxuan Jiang, Aaron Kleinman, Keng-Han Lin, Nadia K Litterman, Jennifer C McCreight, Matthew H McIntyre, Kimberly F McManus, Joanna L Mountain, Elizabeth S Noblin, Carrie A M Northover, Steven J Pitts, G David Poznik, J Fah Sathirapongsasuti, Janie F Shelton, Suyash Shringarpure, Chao Tian, Joyce Tung, Vladimir Vacic, Xin Wang, Catherine H Wilson, Tim Anderson, Steven Bentley, John Dalrymple-Alford, Javed Fowdar, Jacob Gratten, Glenda Halliday, Anjali K Henders, Ian Hickie, Irfahan Kassam, Martin Kennedy, John Kwok, Simon Lewis, George Mellick, Grant Montgomery, John Pearson, Toni Pitcher, Julia Sidorenko, Peter A Silburn, Costanza L Vallerga, Peter M Visscher, Leanne Wallace, Naomi R Wray, Angli Xue, Jian Yang, Futao Zhang

Affiliations

¹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA. Electronic address: mike@datatecnica.com.
² Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
³ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁴ 23andMe, Sunnyvale, CA, USA.
⁵ Department of Human Genetics, Genentech, South San Francisco, CA, USA.
⁶ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK; Department of Clinical and Movement Neuroscience and UCL Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK.
⁷ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK; Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK.
⁸ Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁹ Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK; Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, MI, USA.
¹⁰ Department of Neurology, Baylor College of Medicine, Houston, TX, USA.
¹¹ Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA.
¹² Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases, Tübingen, Germany.
¹³ Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
¹⁴ Department of Human Genetics, McGill University, Montreal, QC, Canada; Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
¹⁵ Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹⁶ Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland; Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland.
¹⁷ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA; The Michael J Fox Foundation, New York, NY, USA.
¹⁸ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Data Tecnica International, Glen Echo, MD, USA.
¹⁹ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Department of Computer Science, University of Illinois Urbana-Champaign, Champaign, IL, USA.
²⁰ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA.
²¹ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK; Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Spain.
²² Institut national de la santé et de la recherche médicale Unité mixte de recherche 1220, Toulouse, France; Paul Sabatier University, Toulouse, France.
²³ Institut national de la santé et de la recherche médicale U1127, CNRS UMR 7225, Paris, France; Sorbonne Université centre national de la recherche médicale, unité mixte de recherche 1127, Paris, France; Assistance Publique Hôpitaux de Paris, Paris, France; Institut du Cerveau et de la Moelle épinière, Paris, France.
²⁴ National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
²⁵ Clinical Neurosciences, Neurology, University of Helsinki, Helsinki, Finland; Helsinki University Hospital, Helsinki, Finland.
²⁶ Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
²⁷ Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway; Jebsen Centre for Psychosis Research, University of Oslo, Oslo, Norway.
²⁸ Department of Human Genetics, McGill University, Montreal, QC, Canada; Montreal Neurological Institute, McGill University, Montreal, QC, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada.
²⁹ Department of Neurology, Baylor College of Medicine, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
³⁰ Department of Molecular Neuroscience, UCL Queen Square Institute of Neurology, London, UK.
³¹ Department of Clinical and Movement Neuroscience and UCL Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK.
³² Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia; Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia.

PMID: 31701892
PMCID: PMC8422160
DOI: 10.1016/S1474-4422(19)30320-5

Abstract

Background: Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.

Methods: We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.

Findings: Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10^-7).

Interpretation: These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.

Funding: The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).

PubMed Disclaimer

Conflict of interest statement

All others have no disclosures or potential conflicts of interest.

Figures

**Figure 1:. Workflow and rationale summary.**
This figure describes study design and rationale behind the analyses included in this report.

**Figure 2:. Manhattan plot.**
The nearest gene to each of the 90 significant variants are labeled in green for previously-identified loci and in blue for novel loci. −log10 P values were capped at 40. Variant points are color coded red and orange, with orange representing significant variants at P 5E-08 and 5E-9 and red representing significant variants at P < 5E-9. The X axis represents the base pair position of variants from smallest to largest per chromosome (–22).

**Figure 3:. Predictive model details.**
A. The odds ratio of developing PD for each quartile of polygenic risk score (PRS) compared to the lowest quartile of genetic risk. B. PRS receiver-operator curves for the more inclusive 1805 variant PRS in the validation dataset as well as in the corresponding training dataset that was used for PRS thresholding and SNP selection.

See this image and copyright information in PMC

Comment in

Challenges in disentangling the genetic background of Parkinson's disease.
König IR. König IR. Lancet Neurol. 2019 Dec;18(12):1069-1070. doi: 10.1016/S1474-4422(19)30387-4. Lancet Neurol. 2019. PMID: 31701887 No abstract available.

References

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1. Keller MF, Saad M, Bras J, Bettella F, Nicolaou N, Simón-Sánchez J, et al.Using genome-wide complex trait analysis to quantify “missing heritability” in Parkinson’s disease. Hum Mol Genet 2012November15;21(22):4996–5009. - PMC - PubMed
1. International Parkinson Disease Genomics Consortium, Nalls MA, Plagnol V, Hernandez DG, Sharma M, Sheerin U-M, et al.Imputation of sequence variants for identification of genetic risks for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet. 2011February19;377(9766):641–9. - PMC - PubMed
1. Nalls MA, McLean CY, Rick J, Eberly S, Hutten SJ, Gwinn K, et al.Diagnosis of Parkinson’s disease on the basis of clinical and genetic classification: a population-based modelling study. Lancet Neurol 2015October;14(10):1002–9. - PMC - PubMed
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Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Collaborators

Affiliations

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical

Miscellaneous