Molecular Genetic Studies of Schizophrenia

Lead Research Organisation: University of Wales
Department Name: UNLISTED

Abstract

Schizophrenia is a common, severe and disabling disorder that in a majority of instances requires long-term medical and social care. It not only results in considerable personal suffering but also has major economic and social impact. In spite of many years of research we still have very little understanding of what causes the disorder. Perhaps the best clue comes from the fact that that we know that genes appear play an important role in influencing who develops schizophrenia from studies of families, twins, and people who have been adopted. However at present, of the 30 000 or so genes each person carries, we do not know which contribute to the disease. Broadly speaking, the main aim of study is to use modern molecular genetic methods to identify some of the specific genes involved in schizophrenia. Identification of these genes should, through further studies, enable researchers to understand what brings schizophrenia about and then to develop more effective treatments.

Technical Summary

Schizophrenia is a common disorder with a lifetime morbid risk of 1%, and more if spectrum disorders are included. Schizophrenia represents a huge source of morbidity, consumes a great deal of medical and social care, yet little is known about its aetiology and therefore it is a priority for further research. Genes have been unequivocally implicated, with heritability estimates of around 80%. Therefore if we are to improve our understanding of this disorder and develop more effective treatments, we must unravel its genetics. The objective of this application is to clone the 2 novel genes for schizophrenia we have localized to chromosomes 10q (LOD 3.89) and 17q (LOD 3.37) by the linkage analysis funded by our previous MRC programme grant. To achieve this, we will narrow the regions showing significant and suggestive linkage by more detailed linkage analyses. This will include the use of denser marker grids (~3cM) across the target regions, analysis of locus-locus interaction, and analysis of co-variation between phenotypic variables and IBD probabilities using a sample of 378 affected sib-pairs. We will then undertake detailed linkage disequilibrium and positional functional candidate gene analyses across the 2 major linkage regions. We will use a combination of high-throughput individual SNP genotyping for LD mapping, and mutation detection, pooled SNP genotyping, allelic expression and individual genotyping for candidate gene analysis. For this new phase in our studies, we have steadily acquired large well-characterized clinical samples of over 2000 unrelated schizophrenic subjects for whom we have DNA. This sample is suitable for case-control association analysis (1100 schizophrenics/1100 controls, 850 of each from the UK/Ireland), family based association analysis (750 complete parent-proband trios in house, and a further 300 trios from collaborators in India) and is unrivalled internationally. Together with the investments in state of the art molecular genetic equipment, bio-statistical/analytical expertise, and the gene analysis methodologies we have developed all primarily from previous MRC funds and from the host institute, our resources puts us internationally at the forefront of the field of schizophrenia genetics, and offers us the realistic opportunity to capitalize upon the results of our previous MRC funded studies. By identifying novel schizophrenia genes, we will contribute to improving our understanding of the origins of this disorder. This will make an impact directly upon the stigma felt by schizophrenic individuals and their families, and provide a platform for developing new treatments that enhance the quality of their lives.

Publications

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publication icon
Asherson P (1994) DRD2 Ser311/Cys311 polymorphism in schizophrenia. in Lancet (London, England)

 
Description DSMV - Membership of Psychotic disorders workgroup
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guidance committee
 
Description Genetic dissection of abnormal oligodendrocyte and myelin fundtion in schizophrenia, NIMH Component Grant of a Silvio O Conte Centre for the Neuroscience of Mental Disorders/National Institutes of Health
Amount £962,510 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start  
 
Description Genomewide association study of schizophrenia/Standford University
Amount £56,716 (GBP)
Organisation Stanford University 
Sector Academic/University
Country United States
Start  
 
Description Genomic and functional analysis of dysbindin in the genesis of schizophrenia
Amount £369,422 (GBP)
Organisation Prostate Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description MRC Centre Grant (Neuropsychiatric Genetics and Genomics)
Amount £2,498,770 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 08/2009 
End 08/2014
 
Description MRC Charity (Molecular genetic studies of schizophrenia)
Amount £2,670 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 01/2007 
End 07/2007
 
Description MRC Research Grant (Molecular Genetics in Schizophrenia)
Amount £2,108,550 (GBP)
Funding ID G0800509 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 12/2008 
End 11/2011
 
Description Population genetic study (CONTE)
Amount £463,480 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 07/2007 
End 05/2012
 
Description Project 3: Population genetic studies
Amount £463,480 (GBP)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start  
 
Description Genomewide association study of Schizophrenia 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution Joint Lead in the Statistical consultancy and analysis, interpretation of results, writing up results - P Holmans and provided a large amount of the data
Collaborator Contribution PI. Gejman Co ordination of the statistical analysis of International consortia on linkage studies of Depression and schizphrenia and Genome wide associaton studies of Schizophrenia (international, multi-centre). All funded by NIH.
Impact Paper PMID 19571809
Start Year 2008
 
Description Genonmic functional analysis of dysbindin in the genesis of schizophrenia 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We have investigated the role of DTNBP1 in schizophrenia by performing a comprehensive genetic screen followed by association analysis for both common and rare genetic variants present at this locus. In addition, we have performed large scale allelic expression studies and in vitro reporter assays to establish which DNA variants are correlated with variation in DTNBP1 gene expression. Finally we also performed both single locus as well as pathway based association analysis using genes that are functionally related to dysbindin in order to investigate its functional role in schizophrenia pathogenesis.
Collaborator Contribution named investigator on this programme grant
Impact Currently this work has yielded 2 published manuscripts (PMID: 19859905 and PMID: 18815010). Additional manuscripts describing the remaining aspects of this work are currently in preparation.
Start Year 2006
 
Description University of Standford - Molecular genetic studies of schizophrenia 
Organisation Stanford University
Country United States 
Sector Academic/University 
PI Contribution subcontract Providing the statistical analysis, interpretation of results, writing up results and providing a large amounts of data.
Collaborator Contribution subcontract Providing the statistical analysis, interpretation of results, writing up results and providing a large amounts of data.
Impact PMIDs 19349958 18371494 19223858 10924404 19976456 12802786 15007391 10924404 11976456 15007391 12802786
 
Description collection of trios in Bulgaria 
Organisation Johnson & Johnson
Department Janssen-Cilag
Country Global 
Sector Private 
PI Contribution During this collaboration we recruited 1000 families with a proband affected with bipolar disorder or schizophrenia, 200 unrelated probands suffering with schizophrneia, 100 unrelated robands suffering with bipolar disorder, and 700 healthy controls. The Cardiff team coordinated all the recruitment and analysis of results.
Collaborator Contribution Sample collection in Bulgaria in collaboration with the Univeristy of Sophia.
Impact This collaboration resulted in the largest trios collection on schizophrenia in world. It has lead to numerous publications, further collaborations with teams from Europe and the USA, and the discovery of several important genetic findings. List of publications that include data from this collaboration: PMID 16631129 PMID 16585465 PMID 16891421 PMID 17044098 PMID 17989066 PMID 18003636 PMID 18298822 PMID 18045777
 
Description Educational Play for Schools 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact This way a play "The Boy Genius" which dealt with issues related to schizophrenia and to genetics, which was performed for schools and teachers, funded by the Wellcome Trust.

Raised profile and anti stigma.
Year(s) Of Engagement Activity 2008
 
Description MDF meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talks and workshops are regulalry given at both local and national MDF meetings

raises profile of research
Year(s) Of Engagement Activity 2008
 
Description Not Mad, Manic 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Participate in BBC Wales' Week In Week Out Documentary

http://www.bdrn.org/Bipolar TV.html
Year(s) Of Engagement Activity 2008
 
Description Pendulum articles 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Two page articles are wrtiten in each edition of the Pendulum magazine - the journal of the Manic Dpression Fellowship

Raising profile of research
Year(s) Of Engagement Activity 2008
 
Description Press releases and Media interviews 
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 Media (as a channel to the public)
Results and Impact multiple interviews and press releases relating to our research in local, national and international - newspapers, journal, radio and television. Describing the research conducted by our teams.

Disseminated information and knowledge and raised the profile of our research.
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Public information website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Developed and host public inforation website about genetics and bipolar disorder to provide information/support following broadcast of Eastenders episodes that deal with genetics Http;//www.bipinfo.org Prof N Craddock and Dr I Jones were advisors to the BBC Eastenders programme writers on the bipolar disorder story lines.

raise profile of research
Year(s) Of Engagement Activity 2009
 
Description Secret life of a Manic Depressive 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Participated in a 2 part BBC Documentary in which Stephen Fry enrolled in our research on camera. http://www.bdrn.org/Stephen Frys participation.html

Documentary won a BAFTA. Increase in participants in our research Raised profile of our project
Year(s) Of Engagement Activity 2006
URL http://bdrn.org/stephen-frys-partisipation/
 
Description Wales Gene Park 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact involved in the Wales Gene Park, of which one of the partners is Techniquest, Cardiff's public centre for science discovery. Public and professional education in relation to genetics, including neurogenetics, is a major part of the Wlaes Gene Park's Mission

raised awareness, combating stigma
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description What's the Problem? 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Participated in MTV programme "What's the Problem?" in which Kerry Katona tried to understand her illness. She enrols in the research on camera Http://dbrn.org/kerry katonas Participation.html

raised profile of our research
Year(s) Of Engagement Activity 2009