. 2016 May;15(6):585-96.

doi: 10.1016/S1474-4422(16)00071-5. Epub 2016 Mar 24.

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

Kin Y Mok¹, Una Sheerin², Javier Simón-Sánchez³, Afnan Salaka⁴, Lucy Chester⁵, Valentina Escott-Price⁵, Kiran Mantripragada⁵, Karen M Doherty⁶, Alastair J Noyce⁷, Niccolo E Mencacci², Steven J Lubbe⁸; International Parkinson's Disease Genomics Consortium (IPDGC); Caroline H Williams-Gray⁹, Roger A Barker⁹, Karin D van Dijk¹⁰, Henk W Berendse¹⁰, Peter Heutink¹¹, Jean-Christophe Corvol¹², Florence Cormier¹², Suzanne Lesage¹², Alexis Brice¹², Kathrin Brockmann¹³, Claudia Schulte¹³, Thomas Gasser¹³, Thomas Foltynie¹⁴, Patricia Limousin¹⁴, Karen E Morrison¹⁵, Carl E Clarke¹⁶, Stephen Sawcer¹⁷, Tom T Warner¹⁸, Andrew J Lees¹⁸, Huw R Morris⁸, Mike A Nalls¹⁹, Andrew B Singleton¹⁹, John Hardy⁷, Andrey Y Abramov², Vincent Plagnol²⁰, Nigel M Williams²¹, Nicholas W Wood²²

Affiliations

¹ 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.
² Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
³ Genetics and Epigenetics of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; Genetics and Epigenetics of Neurodegeneration, Tübingen, Germany.
⁴ 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.
⁵ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
⁶ Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK; Department of Regional Neurosciences, Royal Victoria Hospital, Belfast, UK.
⁷ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
⁸ Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
⁹ John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, University of Cambridge, Cambridge, UK.
¹⁰ Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
¹¹ Genome Biology of Neurodegenerative Diseases, Tübingen, Germany.
¹² 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.
¹³ 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.
¹⁴ Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK.
¹⁵ Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
¹⁶ School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
¹⁷ Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹⁸ Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
¹⁹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
²⁰ UCL Genetics Institute, London, UK.
²¹ 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.
²² Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: n.wood@ucl.ac.uk.

PMID: 27017469
PMCID: PMC4828586
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 et al. Lancet Neurol. 2016 May.

. 2016 May;15(6):585-96.

doi: 10.1016/S1474-4422(16)00071-5. Epub 2016 Mar 24.

Authors

Affiliations

¹ 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.
² Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK.
³ Genetics and Epigenetics of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; Genetics and Epigenetics of Neurodegeneration, Tübingen, Germany.
⁴ 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.
⁵ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK.
⁶ Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK; Department of Regional Neurosciences, Royal Victoria Hospital, Belfast, UK.
⁷ Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
⁸ Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK.
⁹ John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, University of Cambridge, Cambridge, UK.
¹⁰ Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands.
¹¹ Genome Biology of Neurodegenerative Diseases, Tübingen, Germany.
¹² 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.
¹³ 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.
¹⁴ Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK.
¹⁵ Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
¹⁶ School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.
¹⁷ Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK.
¹⁸ Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK.
¹⁹ Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA.
²⁰ UCL Genetics Institute, London, UK.
²¹ 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.
²² Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: n.wood@ucl.ac.uk.

PMID: 27017469
PMCID: PMC4828586
DOI: 10.1016/S1474-4422(16)00071-5

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.

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Figures

**Figure**
Genomic location of the 22q11.2 deletions found in the eight patients with Parkinson's disease and location of the low copy repeat regions UK3 represented an atypical deletion of uncertain relation to 22q11.2 deletion syndrome and was not considered here. Figure drawn using the UCSC Genome Browser.

See this image and copyright information in PMC

Comment in

Chromosomal deletion at 22q11.2 and Parkinson's disease.
Tan EK. Tan EK. Lancet Neurol. 2016 May;15(6):538-40. doi: 10.1016/S1474-4422(16)00115-0. Epub 2016 Mar 24. Lancet Neurol. 2016. PMID: 27017470 No abstract available.
Does 22q11.2 deletion syndrome contribute to the genetic aetiology of Parkinson's disease?
Fung W, Peall KJ. Fung W, et al. J Neurol. 2018 Oct;265(10):2463-2465. doi: 10.1007/s00415-018-9046-x. J Neurol. 2018. PMID: 30238269 Free PMC article. No abstract available.

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

Affiliations

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

Authors

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Abstract

Figures

Comment in

References

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LinkOut - more resources

Full Text Sources

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Medical