Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Mike A Nalls; Nathan Pankratz; Christina M Lill; Chuong B Do; Dena G Hernandez; Mohamad Saad; Anita L DeStefano; Eleanna Kara; Jose Bras; Manu Sharma; Claudia Schulte; Margaux F Keller; Sampath Arepalli; Christopher Letson; Connor Edsall; Hreinn Stefansson; Xinmin Liu; Hannah Pliner; Joseph H Lee; Rong Cheng; International Parkinson's Disease Genomics Consortium (IPDGC); Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI); 23andMe; GenePD; NeuroGenetics Research Consortium (NGRC); Hussman Institute of Human Genomics (HIHG); Ashkenazi Jewish Dataset Investigator; Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE); North American Brain Expression Consortium (NABEC); United Kingdom Brain Expression Consortium (UKBEC); Greek Parkinson's Disease Consortium; Alzheimer Genetic Analysis Group; M Arfan Ikram; John P A Ioannidis; Georgios M Hadjigeorgiou; Joshua C Bis; Maria Martinez; Joel S Perlmutter; Alison Goate; Karen Marder; Brian Fiske; Margaret Sutherland; Georgia Xiromerisiou; Richard H Myers; Lorraine N Clark; Kari Stefansson; John A Hardy; Peter Heutink; Honglei Chen; Nicholas W Wood; Henry Houlden; Haydeh Payami; Alexis Brice; William K Scott; Thomas Gasser; Lars Bertram; Nicholas Eriksson; Tatiana Foroud; Andrew B Singleton

doi:10.1038/ng.3043

Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease

Nat Genet. 2014 Sep;46(9):989-93. doi: 10.1038/ng.3043. Epub 2014 Jul 27.

Authors

Mike A Nalls¹, Nathan Pankratz², Christina M Lill³, Chuong B Do⁴, Dena G Hernandez⁵, Mohamad Saad⁶, Anita L DeStefano⁷, Eleanna Kara⁸, Jose Bras⁸, Manu Sharma⁹, Claudia Schulte¹⁰, Margaux F Keller¹¹, Sampath Arepalli¹¹, Christopher Letson¹¹, Connor Edsall¹¹, Hreinn Stefansson¹², Xinmin Liu¹³, Hannah Pliner¹¹, Joseph H Lee¹⁴, Rong Cheng¹⁴; International Parkinson's Disease Genomics Consortium (IPDGC); Parkinson's Study Group (PSG) Parkinson's Research: The Organized GENetics Initiative (PROGENI); 23andMe; GenePD; NeuroGenetics Research Consortium (NGRC); Hussman Institute of Human Genomics (HIHG); Ashkenazi Jewish Dataset Investigator; Cohorts for Health and Aging Research in Genetic Epidemiology (CHARGE); North American Brain Expression Consortium (NABEC); United Kingdom Brain Expression Consortium (UKBEC); Greek Parkinson's Disease Consortium; Alzheimer Genetic Analysis Group; M Arfan Ikram¹⁵, John P A Ioannidis¹⁶, Georgios M Hadjigeorgiou¹⁷, Joshua C Bis¹⁸, Maria Martinez¹⁹, Joel S Perlmutter²⁰, Alison Goate²¹, Karen Marder²², Brian Fiske²³, Margaret Sutherland²⁴, Georgia Xiromerisiou²⁵, Richard H Myers²⁶, Lorraine N Clark²⁷, Kari Stefansson¹², John A Hardy²⁸, Peter Heutink²⁹, Honglei Chen³⁰, Nicholas W Wood⁸, Henry Houlden⁸, Haydeh Payami³¹, Alexis Brice³², William K Scott³³, Thomas Gasser¹⁰, Lars Bertram³⁴, Nicholas Eriksson⁴, Tatiana Foroud³⁵, Andrew B Singleton¹¹

Collaborators

Mike A Nalls, Vincent Plagnol, Dena G Hernandez, Manu Sharma, Una-Marie Sheerin, Mohamad Saad, Javier Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Roger Barker, Yoav Ben-Shlomo, Henk W Berendse, Daniela Berg, Kailash Bhatia, Rob M A de Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M Bras, Kathrin Brockmann, Janet Brooks, David J Burn, Gavin Charlesworth, Honglei Chen, Patrick F Chinnery, Sean Chong, Carl E Clarke, Mark R Cookson, J Mark Cooper, Jean Christophe Corvol, Carl Counsell, Philippe Damier, Jean-François Dartigues, Panos Deloukas, Günther Deuschl, David T Dexter, Karin D van Dijk, Allissa Dillman, Frank Durif, Alexandra Dürr, Sarah Edkins, Jonathan R Evans, Thomas Foltynie, Jing Dong, Michelle Gardner, J Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Isabel Wurster, Walter Mätzler, Gavin Hudson, Sarah E Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V Jónsson, Jean-Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw R Morris, Karen E Morrison, Ese Mudanohwo, Sean S O'Sullivan, Justin Pearson, Joel S Perlmutter, Hjörvar Pétursson, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Ellen Sidransky, Colin Smith, Chris C A Spencer, Hreinn Stefánsson, Francesco Bettella, Joanna D Stockton, Amy Strange, Kevin Talbot, Carlie M Tanner, Avazeh Tashakkori-Ghanbaria, François Tison, Daniah Trabzuni, Bryan J Traynor, André G Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H Williams-Gray, Sophie Winder-Rhodes, Kári Stefánsson, Maria Martinez, Nicholas W Wood, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B Singleton, S Factor, D Higgins, S Evans, H Shill, M Stacy, J Danielson, L Marlor, K Williamson, J Jankovic, C Hunter, D Simon, P Ryan, L Scollins, R Saunders-Pullman, K Boyar, C Costan-Toth, E Ohmann, L Sudarsky, C Joubert, J Friedman, K Chou, H Fernandez, M Lannon, N Galvez-Jimenez, A Podichetty, K Thompson, P Lewitt, M DeAngelis, C O'Brien, L Seeberger, C Dingmann, D Judd, K Marder, J Fraser, J Harris, J Bertoni, C Peterson, M Rezak, G Medalle, S Chouinard, M Panisset, J Hall, H Poiffaut, V Calabrese, P Roberge, J Wojcieszek, J Belden, D Jennings, K Marek, S Mendick, S Reich, B Dunlop, M Jog, C Horn, R Uitti, M Turk, T Ajax, J Mannetter, K Sethi, J Carpenter, B Dill, L Hatch, K Ligon, S Narayan, K Blindauer, K Abou-Samra, J Petit, L Elmer, E Aiken, K Davis, C Schell, S Wilson, M Velickovic, W Koller, S Phipps, A Feigin, M Gordon, J Hamann, E Licari, M Marotta-Kollarus, B Shannon, R Winnick, T Simuni, A Videnovic, A Kaczmarek, K Williams, M Wolff, J Rao, M Cook, M Fernandez, S Kostyk, J Hubble, A Campbell, C Reider, A Seward, R Camicioli, J Carter, J Nutt, P Andrews, S Morehouse, C Stone, T Mendis, D Grimes, C Alcorn-Costa, P Gray, K Haas, J Vendette, J Sutton, B Hutchinson, J Young, A Rajput, A Rajput, L Klassen, T Shirley, B Manyam, P Simpson, J Whetteckey, B Wulbrecht, D Truong, M Pathak, K Frei, N Luong, T Tra, A Tran, J Vo, A Lang, G Kleiner- Fisman, A Nieves, L Johnston, J So, G Podskalny, L Giffin, P Atchison, C Allen, W Martin, M Wieler, O Suchowersky, S Furtado, M Klimek, N Hermanowicz, S Niswonger, C Shults, D Fontaine, M Aminoff, C Christine, M Diminno, J Hevezi, A Dalvi, U Kang, J Richman, S Uy, J Young, A Dalvi, A Sahay, M Gartner, D Schwieterman, D Hall, M Leehey, S Culver, T Derian, T Demarcaida, S Thurlow, R Rodnitzky, J Dobson, K Lyons, R Pahwa, T Gales, S Thomas, L Shulman, S Reich, W Weiner, K Dustin, K Lyons, C Singer, W Koller, W Weiner, L Zelaya, P Tuite, V Hagen, S Rolandelli, R Schacherer, J Kosowicz, P Gordon, J Werner, C Serrano, S Roque, R Kurlan, D Berry, I Gardiner, R Hauser, J Sanchez-Ramos, T Zesiewicz, H Delgado, K Price, P Rodriguez, S Wolfrath, R Pfeiffer, L Davis, B Pfeiffer, R Dewey, B Hayward, A Johnson, M Meacham, B Estes, F Walker, V Hunt, C O'Neill, B Racette, L Swisher, Cheri Dijamco, Emily Drabant Conley, Elizabeth Dorfman, Joyce Y Tung, David A Hinds, Joanna L Mountain, Anne Wojcicki, M Lew, O Suchowersky, C Klein, L Golbe, J Growdon, G F Wooten, R Watts, M Guttman, B Racette, L Marlor, H Shill, C Singer, S Goldwurm, M H Saint-Hilaire, K Baker, I Litvan, G Nicholson, M Nance, E Drasby, S Isaacson, D Burn, P Pramstaller, J Al-hinti, A Moller, S Sherman, R Roxburgh, J Slevin, J Perlmutter, M H Mark, N Huggins, G Pezzoli, T Massood, I Itin, A Corbett, P Chinnery, K Ostergaard, B Snow, F Cambi, D Kay, A Samii, J Nutt, P Agarwal, J W Roberts, D S Higgins, Eric Molho, Ami Rosen, J Montimurro, E Martinez, A Griffith, V Kusel, D Yearout, S Factor, C Zabetian, L N Clark, X Liu, J H Lee, R Cheng Taub, K Marder, E D Louis, L J Cote, C Waters, B Ford, S Fahn, Jeffery M Vance, Gary W Beecham, Eden R Martin, Karen Nuytemans, Margaret A Pericak-Vance, Jonathan L Haines, Anita DeStefano, Sudha Seshadri, Seung Hoan Choi, Samuel Frank, Joshua C Bis, Bruce M Psaty, Kenneth Rice, W T Longstreth Jr, Thanh G N Ton, Samay Jain, M Arfan Ikram, Cornelia M van Duijn, Albert Hofman, André G Uitterlinden, Vincent J Verlinden, Peter J Koudstaal, Andrew Singleton, Mark Cookson, J Raphael Gibbs, Dena Hernandez, Allissa Dillman, Michael Nalls, Alan Zonderman, Sampath Arepalli, Luigi Ferrucci, Robert Johnson, Dan Longo, Richard O'Brien, Bryan Traynor, Juan Troncoso, Marcel van der Brug, Ronald Zielke, John Hardy, Michael Weale, Mina Ryten, Adaikalavan Ramasamy, Daniah Trabzuni, Colin Smith, Robert Walker, Eleanna Kara, Georgia Xiromerisiou, Efthimios Dardiotis, Vana Tsimourtou, Cleanthe Spanaki, Andreas Plaitakis, Maria Bozi, Leonidas Stefanis, Dimitris Vassilatis, Georgios Koutsis, Marios Panas, Henry Houlden, Georgios M Hadjigeorgiou, Rita Guerreiro, Katie Lunnon, Michelle Lupton, John Powell, Laura Parkkinen, Olaf Ansorge, John Hardy

Affiliations

¹ 1] Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. [2].
² 1] Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. [2].
³ 1] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
⁴ 23andMe, Inc., Mountain View, California, USA.
⁵ 1] Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. [2] Reta Lila Weston Institute, University College London Institute of Neurology, Queen Square, London, UK.
⁶ 1] Department of Biostatistics, University of Washington, Seattle, Washington, USA. [2] INSERM, UMR 1043, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, France. [3] Paul Sabatier University, Toulouse, France.
⁷ 1] Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. [2] Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. [3] National Heart, Lung, and Blood Institute (NHLBI) Framingham Heart Study, Framingham, Massachusetts, USA.
⁸ Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.
⁹ 1] Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. [2] Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹⁰ Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
¹¹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.
¹² deCODE Genetics, Reykjavík, Iceland.
¹³ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA.
¹⁴ The Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA.
¹⁵ 1] Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands. [2] Department of Radiology, Erasmus MC University Medical Center, Rotterdam, the Netherlands. [3] Department of Neurology, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
¹⁶ Stanford Prevention Research Center, Stanford University, Stanford, California, USA.
¹⁷ Neuroscience Unit, Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Greece.
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA.
¹⁹ 1] INSERM, UMR 1043, Centre de Physiopathologie de Toulouse-Purpan, Toulouse, France. [2] Paul Sabatier University, Toulouse, France.
²⁰ 1] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA. [3] Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
²¹ 1] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, USA. [2] Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA. [3] Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. [4] Department of Genetics, Washington University School of Medicine, St. Louis, Missouri, USA.
²² 1] The Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA. [2] Gertrude H. Sergievsky Center, Columbia University Medical Center, New York, New York, USA. [3] Department of Neurology, Columbia University Medical Center, New York, New York, USA. [4] Department of Psychiatry, Columbia University Medical Center, New York, New York, USA.
²³ The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA.
²⁴ Neuroscience Center, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland, USA.
²⁵ 1] Neuroscience Unit, Department of Neurology, Faculty of Medicine, University of Thessaly, Larissa, Greece. [2] Department of Neurology, Papageorgiou Hospital, Thessaloniki, Greece.
²⁶ Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA.
²⁷ 1] Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA. [2] The Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, USA.
²⁸ Reta Lila Weston Institute, University College London Institute of Neurology, Queen Square, London, UK.
²⁹ Genome Biology for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
³⁰ Epidemiology Branch, National Institute of Environmental Health Sciences, US National Institutes of Health, Research Triangle, North Carolina, USA.
³¹ New York State Department of Health Wadsworth Center, Albany, New York, USA.
³² 1] Sorbonne Université, UPMC Université Paris 06, UM 75, INSERM U1127, Institut du Cerveau et de la Moelle, Paris, France. [2] CNRS, UMR 7225, Paris, France. [3] Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, Paris, France.
³³ Department of Human Genetics, University of Miami School of Medicine, Miami, Florida, USA.
³⁴ 1] Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany. [2] School of Public Health, Faculty of Medicine, The Imperial College of Science, Technology and Medicine, London, UK.
³⁵ Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

PMID: 25064009
PMCID: PMC4146673
DOI: 10.1038/ng.3043

Abstract

We conducted a meta-analysis of Parkinson's disease genome-wide association studies using a common set of 7,893,274 variants across 13,708 cases and 95,282 controls. Twenty-six loci were identified as having genome-wide significant association; these and 6 additional previously reported loci were then tested in an independent set of 5,353 cases and 5,551 controls. Of the 32 tested SNPs, 24 replicated, including 6 newly identified loci. Conditional analyses within loci showed that four loci, including GBA, GAK-DGKQ, SNCA and the HLA region, contain a secondary independent risk variant. In total, we identified and replicated 28 independent risk variants for Parkinson's disease across 24 loci. Although the effect of each individual locus was small, risk profile analysis showed substantial cumulative risk in a comparison of the highest and lowest quintiles of genetic risk (odds ratio (OR) = 3.31, 95% confidence interval (CI) = 2.55-4.30; P = 2 × 10(-16)). We also show six risk loci associated with proximal gene expression or DNA methylation.

Publication types

Meta-Analysis
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Case-Control Studies
Genetic Loci*
Genetic Predisposition to Disease
Genome-Wide Association Study / methods
Genotype
Humans
Parkinson Disease / genetics*
Polymorphism, Single Nucleotide
Risk Factors

Abstract

Publication types

MeSH terms

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