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Deletions at 22q11.2 in idiopathic Parkinson's disease : a combined analysis of genome-wide association data

Mok, Kin Y; Sheerin, Una; Simón-Sánchez, Javier; Salaka, Afnan; Chester, Lucy; Escott-Price, Valentina; Mantripragada, Kiran; Doherty, Karen M; Noyce, Alastair J and Mencacci, Niccolo E, et al. (2016) In The Lancet Neurology 15(6). p.96-585
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... (More)

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.

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@article{c095d128-b2f5-493c-b18a-0646adc6a7ee,
  abstract     = {<p>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.</p><p>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.</p><p>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&lt;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).</p><p>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.</p><p>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.</p>},
  author       = {Mok, Kin Y and Sheerin, Una and Simón-Sánchez, Javier and Salaka, Afnan and Chester, Lucy and Escott-Price, Valentina and Mantripragada, Kiran and Doherty, Karen M and Noyce, Alastair J and Mencacci, Niccolo E and Lubbe, Steven J and Williams-Gray, Caroline H and Barker, Roger A and van Dijk, Karin D and Berendse, Henk W and Heutink, Peter and Corvol, Jean-Christophe and Cormier, Florence and Lesage, Suzanne and Brice, Alexis and Brockmann, Kathrin and Schulte, Claudia and Gasser, Thomas and Foltynie, Thomas and Limousin, Patricia and Morrison, Karen E and Clarke, Carl E and Sawcer, Stephen and Warner, Tom T and Lees, Andrew J and Morris, Huw R and Nalls, Mike A and Singleton, Andrew B and Hardy, John and Abramov, Andrey Y and Plagnol, Vincent and Williams, Nigel M and Wood, Nicholas W and , },
  issn         = {1474-4465},
  keyword      = {Journal Article},
  language     = {eng},
  number       = {6},
  pages        = {96--585},
  publisher    = {Lancet Ltd},
  series       = {The Lancet Neurology},
  title        = {Deletions at 22q11.2 in idiopathic Parkinson's disease : a combined analysis of genome-wide association data},
  url          = {http://dx.doi.org/10.1016/S1474-4422(16)00071-5},
  volume       = {15},
  year         = {2016},
}