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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. Epub 2014 Jul 27
Mike A Nalls 1 , Nathan Pankratz 2 , Christina M Lill 3 , Chuong B Do 4 , Dena G Hernandez 5 , Mohamad Saad 6 , Anita L DeStefano 7 , Eleanna Kara 8 , Jose Bras 8 , Manu Sharma 9 , Claudia Schulte 10 , Margaux F Keller 11 , Sampath Arepalli 11 , Christopher Letson 11 , Connor Edsall 11 , Hreinn Stefansson 12 , Xinmin Liu 13 , Hannah Pliner 11 , Joseph H Lee 14 , Rong Cheng 14 , 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 15 , John P A Ioannidis 16 , Georgios M Hadjigeorgiou 17 , Joshua C Bis 18 , Maria Martinez 19 , Joel S Perlmutter 20 , Alison Goate 21 , Karen Marder 22 , Brian Fiske 23 , Margaret Sutherland 24 , Georgia Xiromerisiou 25 , Richard H Myers 26 , Lorraine N Clark 27 , Kari Stefansson 12 , John A Hardy 28 , Peter Heutink 29 , Honglei Chen 30 , Nicholas W Wood 8 , Henry Houlden 8 , Haydeh Payami 31 , Alexis Brice 32 , William K Scott 33 , Thomas Gasser 10 , Lars Bertram 34 , Nicholas Eriksson 4 , Tatiana Foroud 35 , Andrew B Singleton 11
Mike A Nalls 1 , Nathan Pankratz 2 , Christina M Lill 3 , Chuong B Do 4 , Dena G Hernandez 5 , Mohamad Saad 6 , Anita L DeStefano 7 , Eleanna Kara 8 , Jose Bras 8 , Manu Sharma 9 , Claudia Schulte 10 , Margaux F Keller 11 , Sampath Arepalli 11 , Christopher Letson 11 , Connor Edsall 11 , Hreinn Stefansson 12 , Xinmin Liu 13 , Hannah Pliner 11 , Joseph H Lee 14 , Rong Cheng 14 , 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 15 , John P A Ioannidis 16 , Georgios M Hadjigeorgiou 17 , Joshua C Bis 18 , Maria Martinez 19 , Joel S Perlmutter 20 , Alison Goate 21 , Karen Marder 22 , Brian Fiske 23 , Margaret Sutherland 24 , Georgia Xiromerisiou 25 , Richard H Myers 26 , Lorraine N Clark 27 , Kari Stefansson 12 , John A Hardy 28 , Peter Heutink 29 , Honglei Chen 30 , Nicholas W Wood 8 , Henry Houlden 8 , Haydeh Payami 31 , Alexis Brice 32 , William K Scott 33 , Thomas Gasser 10 , Lars Bertram 34 , Nicholas Eriksson 4 , Tatiana Foroud 35 , Andrew B Singleton 11
+ et al

[No authors listed]

Author information
  • 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.

摘要

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.

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