Abstract
SummaryBackgroundParkinson'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.MethodsWe 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.FindingsWe 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).InterpretationClinicians 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.FundingUK 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.
Highlights
Parkinson’s disease is the second most common neurodegenerative disease and is characterised by bradykinesia with resting tremor, stiffness, and gait disturbance, and a range of non-motor features
The US National Institute on Aging (NIA) controls were from the Neurogenetic Repository at the Coriell Institute for Medical Research, which excluded people with schizophrenia and other neurological diseases; unscreened population www.thelancet.com/neurology Vol 15 May 2016
The most common deletion associated with chromosome 22q11.2 deletion syndrome spans about 3 Mb and is flanked by low copy repeats (LCRs) A–D
Summary
Parkinson’s disease is the second most common neurodegenerative disease and is characterised by bradykinesia with resting tremor, stiffness, and gait disturbance, and a range of non-motor features. It involves the aggregation of α-synuclein as Lewy bodies and Lewy neurites in many motor and non-motor brain areas. The identification of rare highly penetrant mutations in genes causing familial Parkinson’s disease has substantially improved our understanding of the pathogenesis of this complex and common disorder.[2] Simultaneously, our understanding of the idiopathic form of the disease has been enhanced by findings from large genome-wide association studies.[3,4,5,6,7,8]
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