title: Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data.
abstract: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2.
  
  
  
  We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients.
  
  
  
  We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005).
  
  
  
  Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both.
  
  
  
  UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Division of Life Science, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, China.
authors.forename: Kin Y
authors.initials: KY
authors.lastname: Mok
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Una
authors.initials: U
authors.lastname: Sheerin
authors.affiliation: Genetics and Epigenetics of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; Genetics and Epigenetics of Neurodegeneration, Tübingen, Germany.
authors.forename: Javier
authors.initials: J
authors.lastname: Simón-Sánchez
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK; Medical Genetics and Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia.
authors.forename: Afnan
authors.initials: A
authors.lastname: Salaka
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Lucy
authors.initials: L
authors.lastname: Chester
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Valentina
authors.initials: V
authors.lastname: Escott-Price
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: Kiran
authors.initials: K
authors.lastname: Mantripragada
authors.affiliation: Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK; Department of Regional Neurosciences, Royal Victoria Hospital, Belfast, UK.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Doherty
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
authors.forename: Alastair J
authors.initials: AJ
authors.lastname: Noyce
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Niccolo E
authors.initials: NE
authors.lastname: Mencacci
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lubbe
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, University of Cambridge, Cambridge, UK.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Williams-Gray
authors.affiliation: John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, University of Cambridge, Cambridge, UK.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
authors.affiliation: Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Karin D
authors.initials: KD
authors.lastname: van Dijk
authors.affiliation: Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
authors.forename: Henk W
authors.initials: HW
authors.lastname: Berendse
authors.affiliation: Genome Biology of Neurodegenerative Diseases, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Heutink
authors.affiliation: Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Center for Scientific Research (CNRS), and Research Unit UMR_S 1127 at Pierre and Marie Curie University University of Paris VI at Sorbonne Universités, Institut du Cerveau et de la Moelle épinière Brain and Spine Institute (ICM), Paris, France; Clinical Investigation Center Unit 1422 at INSERM and AP-HP Hôpital de la Pitié Salpêtrière, Centre d'Investigation Clinique Pitié Neurosciences, Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Corvol
authors.affiliation: Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Center for Scientific Research (CNRS), and Research Unit UMR_S 1127 at Pierre and Marie Curie University University of Paris VI at Sorbonne Universités, Institut du Cerveau et de la Moelle épinière Brain and Spine Institute (ICM), Paris, France; Clinical Investigation Center Unit 1422 at INSERM and AP-HP Hôpital de la Pitié Salpêtrière, Centre d'Investigation Clinique Pitié Neurosciences, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Cormier
authors.affiliation: Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Center for Scientific Research (CNRS), and Research Unit UMR_S 1127 at Pierre and Marie Curie University University of Paris VI at Sorbonne Universités, Institut du Cerveau et de la Moelle épinière Brain and Spine Institute (ICM), Paris, France; Clinical Investigation Center Unit 1422 at INSERM and AP-HP Hôpital de la Pitié Salpêtrière, Centre d'Investigation Clinique Pitié Neurosciences, Paris, France.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Lesage
authors.affiliation: Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Center for Scientific Research (CNRS), and Research Unit UMR_S 1127 at Pierre and Marie Curie University University of Paris VI at Sorbonne Universités, Institut du Cerveau et de la Moelle épinière Brain and Spine Institute (ICM), Paris, France; Clinical Investigation Center Unit 1422 at INSERM and AP-HP Hôpital de la Pitié Salpêtrière, Centre d'Investigation Clinique Pitié Neurosciences, Paris, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Brockmann
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Schulte
authors.affiliation: Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gasser
authors.affiliation: Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Foltynie
authors.affiliation: Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Limousin
authors.affiliation: Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Morrison
authors.affiliation: School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Carl E
authors.initials: CE
authors.lastname: Clarke
authors.affiliation: Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Sawcer
authors.affiliation: Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
authors.forename: Tom T
authors.initials: TT
authors.lastname: Warner
authors.affiliation: Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Lees
authors.affiliation: Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Huw R
authors.initials: HR
authors.lastname: Morris
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Mike A
authors.initials: MA
authors.lastname: Nalls
authors.affiliation: Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
authors.forename: Andrey Y
authors.initials: AY
authors.lastname: Abramov
authors.affiliation: UCL Genetics Institute, London, UK.
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.affiliation: Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK. Electronic address: williamsnm@cf.ac.uk.
authors.forename: Nigel M
authors.initials: NM
authors.lastname: Williams
authors.affiliation: Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: n.wood@ucl.ac.uk.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015897:Comorbidity; D056915:DNA Copy Number Variations; D004062:DiGeorge Syndrome / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*