Identification of copy number variants in familial and pathologically proven PD
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
One of the major initial impacts of the human genome project was how little we understood about genomic diversity. Over the past 2-3 years it has become clear that there is tremendous variation in the numbers of copies of a large proportion of the human genome. There are some striking examples of copy numbers leading to human disease. The best characterised in neurological disease is the rearrangements around PMP22 giving rise to CMT1a and hereditary liability to pressure palsies. In Parkinsons disease, of the currently identified genes,|rearrangements have been found in most of these, including ?-synuclein (1), parkin (2), and PINK1 (3). In fact for ?-synuclein duplication or triplication is the commonest mutational mechanism. Copy number variation (CNVs) can be considered in 2 broad ways. First there are rare occurrences (as above) where the duplication or deletion of genomic region may lead to a highly penetrant mendelian form of disease. In the second, there is the potential role of common rearrangements in susceptibility to disease. In the case of PD the rearrangements|listed above were all found after classical positional cloning strategies had identified them as PD genes and it was during the genetic characterisation of these genes that the rearrangements were demonstrated. Recent advances in genetic technologies allows for a rapid, robust genome wide search for CNVs. We plan to screen our series of patients for CNVs. In essence we will look in our recessive families for CNV, with particular emphasis on homozygous rearrangements. This work complements the objectives of subproject 2. We are also aware that single heterozygous rearrangements can cause autosomal dominant disease (eg ?-syn). Therefore, in parallel with subproject 1 we will interrogate our AD PD families. Finally the role of common CNVs has not been assessed in PD and we will adopt a genome wide search in 400 cases of sporadic pathologically proven PD.|
People |
ORCID iD |
Nicholas Wood (Principal Investigator) |
Publications
International Parkinson's Disease Genomics Consortium (IPDGC)
(2011)
A two-stage meta-analysis identifies several new loci for Parkinson's disease.
in PLoS genetics
Kara E
(2014)
Assessment of Parkinson's disease risk loci in Greece.
in Neurobiology of aging
Keller MF
(2012)
Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease.
in Human molecular genetics
Kojovic M
(2012)
Young-onset parkinsonism due to homozygous duplication of a-synuclein in a consanguineous family.
in Movement disorders : official journal of the Movement Disorder Society
Ling H
(2011)
An intragenic duplication in guanosine triphosphate cyclohydrolase-1 gene in a dopa-responsive dystonia family
in Movement Disorders
Lubbe SJ
(2016)
Additional rare variant analysis in Parkinson's disease cases with and without known pathogenic mutations: evidence for oligogenic inheritance.
in Human molecular genetics
Mencacci NE
(2015)
Reply: Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
in Brain : a journal of neurology
Mencacci NE
(2014)
Parkinson's disease in GTP cyclohydrolase 1 mutation carriers.
in Brain : a journal of neurology
Mencacci NE
(2015)
A missense mutation in KCTD17 causes autosomal dominant myoclonus-dystonia.
in American journal of human genetics
Mittag F
(2012)
Use of support vector machines for disease risk prediction in genome-wide association studies: concerns and opportunities.
in Human mutation
Description | 2011 - MRC - Clinical Research Fellowship - amcneill |
Amount | £129,110 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 07/2011 |
End | 07/2013 |
Description | 2011 - NIHR - Equipment Grant - nwood |
Amount | £339,000 (GBP) |
Organisation | National Institute for Health Research |
Sector | Public |
Country | United Kingdom |
Start | 06/2011 |
End | 06/2012 |
Description | 2011 - PUK - Filling the genetic gaps in Parkinson's - nwood |
Amount | £315,000 (GBP) |
Funding ID | G-1107 |
Organisation | Parkinson's UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 12/2011 |
End | 11/2013 |
Description | 2011 - WT - Equipment Grant - nwood |
Amount | £661,636 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2011 |
End | 12/2015 |
Title | Copy number variation database |
Description | Database of patients with copy number variation |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2010 |
Provided To Others? | Yes |
Impact | Not yet |
Description | International Parkinson's disease consortium |
Organisation | Eberhard Karls University of Tübingen |
Department | Neurogenetics |
Country | Germany |
Sector | Academic/University |
PI Contribution | Principal UK contributor |
Collaborator Contribution | Building international consortium |
Impact | Publication in Nature genetics and Hum Mol genetics and a further recent submission |
Start Year | 2009 |
Description | International Parkinson's disease consortium |
Organisation | National Institutes of Health (NIH) |
Department | National Institute on Aging |
Country | United States |
Sector | Public |
PI Contribution | Principal UK contributor |
Collaborator Contribution | Building international consortium |
Impact | Publication in Nature genetics and Hum Mol genetics and a further recent submission |
Start Year | 2009 |
Description | protein phosphorylation in PD |
Organisation | University of Dundee |
Department | MRC Protein Phosphorylation and Ubiquitylation Unit |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Integrated biochemical approach to evaluating kinases involved in parkinsons pathophysiology |
Impact | Recent successful strategic award- Wellcome trust/MRC- neurodegenerative diseases |
Start Year | 2008 |
Description | Neuromedia Corner |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Interviewed for a webcast explaining the recent advances in the genetics of Parkinson's Disease. unknown |
Year(s) Of Engagement Activity | 2010 |
Description | Parkinson's UK Website |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Details on the finding of 5 genes which are involved in Parkinson's disease Picked up for UK press release |
Year(s) Of Engagement Activity | 2011 |
Description | Parkinson's UK Website |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Information disseminated to the general public about how changes in PINK1 can lead to Parkinson's disease Interest from PD society member visits to lab about the work that is being undertaken |
Year(s) Of Engagement Activity | 2010 |
Description | Telegraph Article |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | Press release of the findings of genetic studies of Parkinson's disease Increased interest from general public on PD genetic research |
Year(s) Of Engagement Activity | 2011 |