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

Kin Y Mok; Una Sheerin; Javier Simón-Sánchez; Afnan Salaka; Lucy Chester; Valentina Escott-Price; Kiran Mantripragada; Karen M Doherty; Alastair J Noyce; Niccolo E Mencacci; Steven J Lubbe; Caroline H Williams-Gray; Roger A Barker; Karin D van Dijk; Henk W Berendse; Peter Heutink; Jean-Christophe Corvol; Florence Cormier; Suzanne Lesage; Alexis Brice; Kathrin Brockmann; Claudia Schulte; Thomas Gasser; Thomas Foltynie; Patricia Limousin; Karen E Morrison; Carl E Clarke; Stephen Sawcer; Tom T Warner; Andrew J Lees; Huw R Morris; Mike A Nalls; Andrew B Singleton; John Hardy; Andrey Y Abramov; Vincent Plagnol; Nigel M Williams; Nicholas W Wood; International Parkinson's Disease Genomics Consortium (IPDGC)

doi:10.1016/S1474-4422(16)00071-5

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

Kin Y Mok, Una Sheerin, Javier Simón-Sánchez, Afnan Salaka, Lucy Chester, Valentina Escott-Price, Kiran Mantripragada, Karen M Doherty, Alastair J Noyce, Niccolo E Mencacci, Steven J Lubbe, Caroline H Williams-Gray, Roger A Barker, Karin D van Dijk, Henk W Berendse, Peter Heutink, Jean-Christophe Corvol, Florence Cormier, Suzanne Lesage, Alexis BriceKathrin Brockmann, Claudia Schulte, Thomas Gasser, Thomas Foltynie, Patricia Limousin, Karen E Morrison, Carl E Clarke, Stephen Sawcer, Tom T Warner, Andrew J Lees, Huw R Morris, Mike A Nalls, Andrew B Singleton, John Hardy, Andrey Y Abramov, Vincent Plagnol, Nigel M Williams, Nicholas W Wood, International Parkinson's Disease Genomics Consortium (IPDGC)

Research output: Contribution to journal › Article › peer-review

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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
Journal	The Lancet Neurology
Early online date	24 Mar 2016
DOIs	https://doi.org/10.1016/S1474-4422(16)00071-5
Publication status	E-pub ahead of print - 24 Mar 2016

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Mok, K. Y., Sheerin, U., Simón-Sánchez, J., Salaka, A., Chester, L., Escott-Price, V., Mantripragada, K., Doherty, K. M., Noyce, A. J., Mencacci, N. E., Lubbe, S. J., Williams-Gray, C. H., Barker, R. A., van Dijk, K. D., Berendse, H. W., Heutink, P., Corvol, J-C., Cormier, F., Lesage, S., ... International Parkinson's Disease Genomics Consortium (IPDGC) (2016). Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data. The Lancet Neurology. Advance online publication. https://doi.org/10.1016/S1474-4422(16)00071-5

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

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.",

author = "Mok, {Kin Y} and Una Sheerin and Javier Sim{\'o}n-S{\'a}nchez and Afnan Salaka and Lucy Chester and Valentina Escott-Price and Kiran Mantripragada 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 Peter Heutink and Jean-Christophe Corvol and Florence Cormier and Suzanne Lesage and Alexis Brice and Kathrin Brockmann and Claudia Schulte and Thomas Gasser and Thomas Foltynie and Patricia Limousin and Morrison, {Karen E} and Clarke, {Carl E} and Stephen Sawcer and Warner, {Tom T} and Lees, {Andrew J} and Morris, {Huw R} and Nalls, {Mike A} and Singleton, {Andrew B} and John Hardy and Abramov, {Andrey Y} and Vincent Plagnol and Williams, {Nigel M} and Wood, {Nicholas W} and {International Parkinson's Disease Genomics Consortium (IPDGC)}",

year = "2016",

month = mar,

day = "24",

doi = "10.1016/S1474-4422(16)00071-5",

language = "English",

journal = "The Lancet Neurology",

issn = "1474-4422",

publisher = "Elsevier",

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Mok, KY, Sheerin, U, Simón-Sánchez, J, Salaka, A, Chester, L, Escott-Price, V, Mantripragada, K, Doherty, KM, Noyce, AJ, Mencacci, NE, Lubbe, SJ, Williams-Gray, CH, Barker, RA, van Dijk, KD, Berendse, HW, Heutink, P, Corvol, J-C, Cormier, F, Lesage, S, Brice, A, Brockmann, K, Schulte, C, Gasser, T, Foltynie, T, Limousin, P, Morrison, KE, Clarke, CE, Sawcer, S, Warner, TT, Lees, AJ, Morris, HR, Nalls, MA, Singleton, AB, Hardy, J, Abramov, AY, Plagnol, V, Williams, NM, Wood, NW & International Parkinson's Disease Genomics Consortium (IPDGC) 2016, 'Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data', The Lancet Neurology. https://doi.org/10.1016/S1474-4422(16)00071-5

TY - JOUR

T1 - Deletions at 22q11.2 in idiopathic Parkinson's disease

T2 - a combined analysis of genome-wide association data

AU - Mok, Kin Y

AU - Sheerin, Una

AU - Simón-Sánchez, Javier

AU - Salaka, Afnan

AU - Chester, Lucy

AU - Escott-Price, Valentina

AU - Mantripragada, Kiran

AU - Doherty, Karen M

AU - Noyce, Alastair J

AU - Mencacci, Niccolo E

AU - Lubbe, Steven J

AU - Williams-Gray, Caroline H

AU - Barker, Roger A

AU - van Dijk, Karin D

AU - Berendse, Henk W

AU - Heutink, Peter

AU - Corvol, Jean-Christophe

AU - Cormier, Florence

AU - Lesage, Suzanne

AU - Brice, Alexis

AU - Brockmann, Kathrin

AU - Schulte, Claudia

AU - Gasser, Thomas

AU - Foltynie, Thomas

AU - Limousin, Patricia

AU - Morrison, Karen E

AU - Clarke, Carl E

AU - Sawcer, Stephen

AU - Warner, Tom T

AU - Lees, Andrew J

AU - Morris, Huw R

AU - Nalls, Mike A

AU - Singleton, Andrew B

AU - Hardy, John

AU - Abramov, Andrey Y

AU - Plagnol, Vincent

AU - Williams, Nigel M

AU - Wood, Nicholas W

AU - International Parkinson's Disease Genomics Consortium (IPDGC)

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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.

AB - 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.

U2 - 10.1016/S1474-4422(16)00071-5

DO - 10.1016/S1474-4422(16)00071-5

M3 - Article

C2 - 27017469

SN - 1474-4422

JO - The Lancet Neurology

JF - The Lancet Neurology

ER -

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

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