Association analysis of complex traits: genome screen using pooled DNA on microarrays followed by haplotype fine-mapping

Lead Research Organisation: King's College London
Department Name: Unlisted

Abstract

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Technical Summary

Aims: Identification of genes involved in complex traits has proved to be a considerable challenge. There has been an explosion in the data available and simultaneous analysis of multiple variants can increase the efficiency of tests as well as improve the chance of identifying causal variants rather than those simply in linkage disequilibrium with causal variants. However as a limited number of techniques are available to perform such analyses, I intend to develop two novel methods during this fellowship. I will explore the behaviour of the resultant tests using both simulated and real data as well as writing user-friendly computer programs to facilitate their widespread use.
Design and methodology: Analysis of multiple markers genotyped in pooled samples: Studies are now being designed that combine the use of pooled DNA samples and multiplex technologies to screen many thousands of markers for association with complex traits. Analysis techniques for pooled allele frequencies have only been derived for single markers, this approach can be problematic where large numbers of correlated markers are being tested. Methods for multi-marker analysis have been suggested but none has been adequately tested and none has been adapted to incorporate published linkage disequilibrium information. We have demonstrated the application of meta-regression to the analysis association between complex traits and single markers, in this fellowship I will extend this technique to deal with multiple correlated markers.
Efficient grouping of multi-marker haplotypes: The intensive search for causative variants in associated regions involves genotyping multiple tightly linked markers. Although haplotype analysis can be carried out on such data it is often inefficient due to the presence of large numbers of rare haplotypes. Rare haplotypes are sometimes grouped in an attempt to gain power but the grouping of haplotypes with different effects could mask association. Investigation has already been undertaken into different ways of clustering related haplotypes. I intend to develop approaches using cladograms further and to explore the relative benefits of different methods as well as the techniques used to analyse the data from the resultant groups.
Data: As well as using simulated and HapMap data I will use data from an association study of mild mental impairment in which we are screening 500,000 markers in 5,000 twins (PI: Prof Plomin) and data from the fine-mapping study of linkage peaks identified in our genome screen of depression (PI: Prof McGuffin).
Scientific and medical opportunities: Identifying genes involved in complex traits will lead to increased understanding of the aetiology of these diseases leading to an increase in the ability of clinicians to prevent, cure and treat these disorders.

Publications

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Chen W (2008) DSM-IV combined type ADHD shows familial association with sibling trait scores: a sampling strategy for QTL linkage. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

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Cohen-Woods S (2010) The Bipolar Association Case-Control Study (BACCS) and meta-analysis: No association with the 5,10-Methylenetetrahydrofolate reductase gene and bipolar disorder. in American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics

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Curtis D (2006) Program report: GENECOUNTING support programs. in Annals of human genetics

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Curtis D (2008) A simple method for assessing the strength of evidence for association at the level of the whole gene. in Advances and applications in bioinformatics and chemistry : AABC

 
Title CLUMPHAP 
Description Method for performing association analysis using clustered haplotypes. Implemented in a freely available program called CLUMPHAP. 
Type Of Material Data analysis technique 
Year Produced 2008 
Provided To Others? Yes  
Impact Other researchers have found it a useful tool for exploring their data. 
 
Title Power of pooling for twin pairs 
Description Specialised method for looking at the power of pooling for twin pairs. 
Type Of Material Data analysis technique 
Year Produced 2006 
Provided To Others? Yes  
Impact This method was used to help design studies using the TEDs project which has 6000 twin pairs. 
 
Title Power of pooling given genotype correlation 
Description Specialised method for looking at the power of pooling given the correlation between pooled and individual genotypes. 
Type Of Material Data analysis technique 
Year Produced 2009 
Provided To Others? Yes  
Impact This work is quite new and I am not aware of others using it yet. 
 
Title Technique of meta-analysis for pooled data 
Description Method for incorporating extra information about DNA in pools e.g. phenotype severity, into the analysis. 
Type Of Material Data analysis technique 
Year Produced 2006 
Provided To Others? Yes  
Impact There have been a number of publications that have employed this technique e.g 16082702 
 
Description Other collaborations 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution I either undertook or helped to direct the analysis in these collaborations.
Collaborator Contribution I have been involved in a number of collaborations on applied projects which have ensured my methodological research is always addressing questions that are relevant to people with data analysis.
Impact 19181679, 17267777. 18996918, 17549529, 20552676
 
Description PhD Student 2 
Organisation King's College London
Department MRC Social Genetic and Developmental Psychiatry Centre (SDGP)
Country United Kingdom 
Sector Academic/University 
PI Contribution I helped supervise this student during his PhD and this has resulted in a publication (18188666).
Collaborator Contribution This student completed a PhD which I helped to supervise in collaboration with the dean of the IOP.
Impact 18188666
 
Description PhD student 1 
Organisation King's College London
Department Institute of Psychiatry, Psychology & Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution I helped supervise this student during his PhD and this has resulted in a publication (19771574).
Collaborator Contribution Student 1 is undertaking a PhD that I am helping to supervise in collaboration with the head of Biostats.
Impact 19771574
 
Description QMUL 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution A number of projects were undertaken with the research groups discussing the projects and writing the papers jointly.
Collaborator Contribution Academic
Impact 18395815, 18355389, 18205893, 17490491, 17044864, 16626337.
 
Description Radboud University 
Organisation Radboud University Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution I supervised a visiting student from Radboud University when she spent 3 months in the UK.
Collaborator Contribution Academic
Impact 17425620
Start Year 2006
 
Description Supervisor 
Organisation University of Hong Kong
Country Hong Kong 
Sector Academic/University 
PI Contribution My supervisor on the fellowship I am currently reporting on moved to Hong Kong during the course of the fellowship but we continued to collaborate. I designed and implemented two main research projects, one on haplotype clustering and the other on the analysis of pooled samples. For the first I developed a technique to cluster haplotypes and analyse them and I helped to implement this is a C++ program that has been made freely available. This work is published (18395815). The second theme encompassed two projects. (a) I investigated the power of pooling in large twin studies and developed a meta-analytical technique to study quantitative traits in studies using pooled DNA (16479323); (b) I investigated the properties of the bivariate distribution of test stats from pooled data and individually gentoyped data (19172081). Although most of my work related to the development of methodology I was also involved in the analysis of a large case control bi-polar sample. We have found association in a region previously highlighted in linkage studies. The paper is currently with reviewers.
Collaborator Contribution Academic guidance
Impact 18395815, 16479323, 19172081.
 
Description Washington University in St Louis 
Organisation Washington University in St Louis
Country United States 
Sector Academic/University 
PI Contribution I visited Washington University in St Louis for 2 months in 2007. We collaborated on two projects. On both projects I did the work under the supervision and was provided with data. One paper is published (19172081) the other is in press.
Collaborator Contribution Academic and samples
Impact 19172081, 20872768
Start Year 2007
 
Description Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact I wrote a press release about my paper on haplotype clustering for the IOP web page.

None
Year(s) Of Engagement Activity 2008