Abstract
Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 585-596 |
| Number of pages | 12 |
| Journal | The Lancet Neurology |
| Volume | 15 |
| Issue number | 6 |
| DOIs | |
| State | Published - May 1 2016 |
Funding
This work was supported financially by a Medical Research Council (MRC) and Wellcome Trust Strategic Award (WT089698/Z/09/Z) to the UK Parkinson's Disease Consortium, whose members are from the UCL Institute of Neurology, University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee; and a grant from the Karin och Sten Morstedt CBD Solutions AB. The work was undertaken at University College London Hospitals and University College London, who receive support from the Department of Health's National Institute for Health Research (NIHR) Biomedical Research Centres funding streams. This work was also supported by a Parkinson's UK project grant (G1309) and a studentship from the Saudi Cultural Bureau (Ref 15600). KYM was partly supported by ERA-Net NEURON and is supported by a grant from the Karin och Sten Mortstedt CBD Solutions AB. AS has received grants from the Saudi Cultural Bureau. VE-P, KM, and AJN have received grants from Parkinson's UK. SJL, HRM, and NMW, are funded by Parkinson's UK (Grants 8047 and J-1101) and the MRC UK (G0700943, G1100643). HRM has also received grants from the MRC UK, the Welsh Assembly Government, the Motor Neurone Disease Association, the PSP Association, and the Drake Foundation. CHW-G has received a clinical research fellowship from the Patrick Berthoud Trust; an NIHR Biomedical Research Centre award to the University of Cambridge, Cambridge University Hospitals NHS Trust; grants from the MRC, Wellcome Trust, Parkinson's UK, the Rosetrees Trust, Academy of Medical Sciences, and Addenbrooke's Charitable Trust; and travel expenses and faculty stipend from the Movement Disorder Society. KDvD and HWB have received grants from the Dutch Parkinson Foundation (Parkinson Vereniging) and Neuroscience Campus Amsterdam. J-CC has received grants from Agence Nationale pour la Recherche (ANR-10-IAIHU-06), the French Ministry of Health, and the Michael J Fox Foundation. KB has received grants from the University of T\u00FCbingen, the German Society of Parkinson's disease, and the Michael J Fox Foundation. AJL has received grants from the PSP Association, The Reta Lila Weston Trust, and The Reta Lila Howard Foundation. KEM has received support from the MRC and NIHR. ABS has received support from the Intramural Research Program of the National Institute on Aging, National Institutes of Health, a part of the Department of Health and Human Services (ZO1 AG000949). We thank the patients and control individuals whose participation made this research possible, Mark Gaskin for his efforts in managing the DNA samples and Hallgeir Jonvik for maintaining the database, both at the UCL Department of Molecular Neuroscience. SS would like to thank Cambridge NIHR Biomedical Research Centre for their support. AJN has received grants from Elan/Prothena Pharmaceuticals, grants and non-financial support from GE Healthcare, and personal fees from Office Octopus. CHW-G has received honoraria from Lundbeck, travel grants from UCB Pharma, and grants from Stevenage Biosciences Catalyst. J-CC has received grants from Ipsen and Sanofi -Aventis; non-financial support from Teva, Lundbeck, UCB, and Novartis; and personal fees from AbbVie, Pfizer, and Zambon. KB has received personal fees from Lundbeck. TF has received personal fees from Medtronic, Oxford Biomedica, and UCB Pharma. AJL has received honoraria from Britannia Pharmaceuticals, Roche, Novartis, Boehringer Ingelheim, Lundbeck, Teva, Solvay, GlaxoSmithKline, Ipsen, Allergan, Orion, Bial, AbbVie Lucid, UCB, and Nordicinfu. HRM has received personal fees from Teva, AbbVie, UCB, Boehringer Ingelheim, GlaxoSmithKline, and Acorda; non-financial support from Teva and Medtronic; and grants from the Ipsen Fund and CBD Solutions. Additionally, HRM is a co-applicant on a pending patent application related to C9ORF72 (Method for diagnosing a neurodegenerative disease; PCT/GB2012/052140). All other authors declare no competing interests.This work was supported financially by a Medical Research Council (MRC) and Wellcome Trust Strategic Award (WT089698/Z/09/Z) to the UK Parkinson\u2019s Disease Consortium, whose members are from the UCL Institute of Neurology, University of Sheffield, and the MRC Protein Phosphorylation Unit at the University of Dundee; and a grant from the Karin och Sten Morstedt CBD Solutions AB. The work was undertaken at University College London Hospitals and University College London, who receive support from the Department of Health\u2019s National Institute for Health Research (NIHR) Biomedical Research Centres funding streams. This work was also supported by a Parkinson\u2019s UK project grant (G1309) and a studentship from the Saudi Cultural Bureau (Ref 15600). KYM was partly supported by ERA-Net NEURON and is supported by a grant from the Karin och Sten Mortstedt CBD Solutions AB. AS has received grants from the Saudi Cultural Bureau. VE-P, KM, and AJN have received grants from Parkinson\u2019s UK. SJL, HRM, and NMW, are funded by Parkinson\u2019s UK (Grants 8047 and J-1101) and the MRC UK (G0700943, G1100643). HRM has also received grants from the MRC UK, the Welsh Assembly Government, the Motor Neurone Disease Association, the PSP Association, and the Drake Foundation. CHW-G has received a clinical research fellowship from the Patrick Berthoud Trust; an NIHR Biomedical Research Centre award to the University of Cambridge, Cambridge University Hospitals NHS Trust; grants from the MRC, Wellcome Trust, Parkinson\u2019s UK, the Rosetrees Trust, Academy of Medical Sciences, and Addenbrooke\u2019s Charitable Trust; and travel expenses and faculty stipend from the Movement Disorder Society. KDvD and HWB have received grants from the Dutch Parkinson Foundation (Parkinson Vereniging) and Neuroscience Campus Amsterdam. J-CC has received grants from Agence Nationale pour la Recherche (ANR-10-IAIHU-06), the French Ministry of Health, and the Michael J Fox Foundation. KB has received grants from the University of T\u00FCbingen, the German Society of Parkinson\u2019s disease, and the Michael J Fox Foundation. AJL has received grants from the PSP Association, The Reta Lila Weston Trust, and The Reta Lila Howard Foundation. KEM has received support from the MRC and NIHR. ABS has received support from the Intramural Research Program of the National Institute on Aging, National Institutes of Health, a part of the Department of Health and Human Services (ZO1 AG000949). We thank the patients and control individuals whose participation made this research possible, Mark Gaskin for his eff orts in managing the DNA samples and Hallgeir Jonvik for maintaining the database, both at the UCL Department of Molecular Neuroscience. SS would like to thank Cambridge NIHR Biomedical Research Centre for their support.
ASJC Scopus subject areas
- Clinical Neurology