ERANET 1 NEURON 3: Identification of copy number variants in familial and pathologically proven PD
Lead Research Organisation:
University College London
Department Name: UNLISTED
Abstract
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 Parkinson’s disease, of the currently identified genes,
rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-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 a-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.
rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-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 a-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.
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 Parkinson’s disease, of the currently identified genes,
rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-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 a-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.
rearrangements have been found in most of these, including a-synuclein (1), parkin (2), and PINK1 (3). In fact for a-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 a-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
Gandhi S
(2010)
Genome-wide association studies: the key to unlocking neurodegeneration?
in Nature neuroscience
Renton AE
(2011)
A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD.
in Neuron
International Parkinson Disease Genomics Consortium
(2011)
Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.
in Lancet (London, England)
Ling H
(2011)
An intragenic duplication in guanosine triphosphate cyclohydrolase-1 gene in a dopa-responsive dystonia family
in Movement Disorders
Devine MJ
(2011)
Parkinson's disease and cancer: two wars, one front.
in Nature reviews. Cancer
International Parkinson's Disease Genomics Consortium (IPDGC)
(2011)
A two-stage meta-analysis identifies several new loci for Parkinson's disease.
in PLoS genetics
UK Parkinson's Disease Consortium
(2011)
Dissection of the genetics of Parkinson's disease identifies an additional association 5' of SNCA and multiple associated haplotypes at 17q21.
in Human molecular genetics
Charlesworth G
(2012)
Mutations in ANO3 cause dominant craniocervical dystonia: ion channel implicated in pathogenesis.
in American journal of human genetics
Gardiner AR
(2012)
PRRT2 gene mutations: from paroxysmal dyskinesia to episodic ataxia and hemiplegic migraine.
in Neurology
Plagnol V
(2012)
A robust model for read count data in exome sequencing experiments and implications for copy number variant calling.
in Bioinformatics (Oxford, England)
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 |