The effect of common disease associated genetic variants on transcriptomic and early life phenotypes

Lead Research Organisation: University of Bristol
Department Name: Social Medicine

Abstract

Scientists have recently made substantial progress in identifying genes that increase the risk of ?common diseases? like diabetes, heart disease, asthma, and various forms of cancer. However, in many cases the biological pathways through which these genes exert their negative effects are unknown. The aim of this proposal is to better characterize the biological systems that genetically predispose some people to future disease. 101 genetic markers associated with common diseases will be genotyped in 10,000 children from the Avon Longitudinal Study of Parents and their Children (ALSPAC). ALSPAC is a very large study containing detailed information on hundreds of biological variables relevant to future health, including measures of genetic functioning in 1000 of these children. The planned research revolves around investigating the genetic markers (i.e. which are associated with disease), and their relationship to the biological variables and measures of genetic functioning contained within ALSPAC. In order to integrate the many different data types and make maximum use of the information, a combination of existing and new statistical methodology will be employed. In the event that an interesting biological effect is identified, the experiment will be repeated in two other large studies that contain similar information- the RAINE study in Australia, and the Pelotas study in Brazil. This will give an indication of whether the finding is genuine or whether it was simply due to chance. It is expected that this sort of approach will increase our understanding of the causal pathways involved in disease etiology, and enhance our ability to detect disease-genes above and beyond what could be achieved through standard methods alone.

Technical Summary

Explosive growth in knowledge related to the genomic architecture of disease and genotyping technologies coupled with effective study designs has resulted in a rapidly expanding list of genes known to affect complex human phenotypes and diseases. However, in many cases the underlying biological mechanisms responsible for the development of disease and consistently observed associations remain unknown. The aim of this application is to genotype SNPs that are robustly associated with disease in several large population based cohorts in which detailed transcriptomic and endophenotype measures are available, with the intention of elucidating the biological pathways through which these genetic variants predispose to future disease. 101 SNPs reliably associated with common diseases will be genotyped in 10,000 offspring from the Avon Longitudinal Study of Parents and their Children (ALSPAC) cohort. These children have been measured longitudinally on hundreds of detailed endophenotypes relevant to future disease development (i.e. cardiovascular disease, obesity, diabetes, cancer, psychiatric morbidity and neuro-cognitive functioning), and in the case of 1000 of them, will also have genome-wide mRNA expression levels assayed in lymphoblastoid cell lines (~48,000 transcripts).

SNPs will be tested for association with transcriptomic and endophenotype variables using standard linear regression in the case of continuous measures, and logistic regression in the case of binary outcomes. Putative associations will be tested for replication in the Australian RAINE (N = 3,000) and/or Brazillian Pelotas cohorts (N = 11,000 in total) depending on the availability of similar endophenotypes. Complex relationships between SNPs, mRNA levels and endophenotypes will be investigated more thoroughly by existing and novel multivariate approaches including the construction of Bayesian co-expression gene networks. In this regard, a central aim of the proposal will be the development and characterization of statistical methodology for analyzing high dimensional multivariate genetic, transcriptomic and phenotypic data. Statistical tools and software for the (multivariate) analysis of genetic data will be made available to the academic community. It is expected that integrating information from genetic, transcriptomic and phenotypic sources will not only identify molecular pathways involved in disease pathogenesis, but also significantly enhance ability to detect disease-gene associations above and beyond what could be achieved through genetic association studies alone.

Publications

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Australo-Anglo-American Spondyloarthritis Consortium (TASC) (2010) Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. in Nature genetics

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Bouzigon E (2010) Meta-analysis of 20 genome-wide linkage studies evidenced new regions linked to asthma and atopy. in European journal of human genetics : EJHG

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Chen L (2009) Genetic variants in the vitamin d receptor are associated with advanced prostate cancer at diagnosis: findings from the prostate testing for cancer and treatment study and a systematic review. in Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

 
Description BBSRC Research Grant
Amount £1,480,134 (GBP)
Funding ID BB/I025751/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2011 
End 09/2013
 
Description MRC Project Grant
Amount £1,280,074 (GBP)
Funding ID G0701603 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start  
 
Description NHMRC Project Grant
Amount £763,830 (GBP)
Funding ID 511132 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2008 
End 12/2010
 
Description NHMRC, Project Grant
Amount $910,400 (AUD)
Funding ID 628582 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2009 
End 12/2013
 
Description NHMRC, Project Grant
Amount $545,000 (AUD)
Funding ID 569829 
Organisation National Health and Medical Research Council 
Sector Public
Country Australia
Start 01/2009 
End 12/2011
 
Description Project Grant, Arthritis Council UK
Amount £256,447 (GBP)
Funding ID MP/20244 
Organisation Versus Arthritis 
Start 05/2013 
End 04/2016
 
Description Wellcome Trust Case Control Consortium 2
Amount £73,925 (GBP)
Funding ID 084767 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Case Control Consortium 2
Amount £1,055,400 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Wellcome Trust Project Grant
Amount £2,451,624 (GBP)
Funding ID WT088806 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description EAGLE Consortium 
Organisation Helmholtz Association of German Research Centres
Department Helmholtz Zentrum Munchen
Country Germany 
Sector Public 
PI Contribution Organizing and international meta-analysis of Eczema data from pediatric cohorts
Collaborator Contribution Provision of genetic data for analysis
Impact 22197932 23817569
Start Year 2009
 
Description EGG Consortium 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of genome-wide association data
Collaborator Contribution Discovery of genetic loci influencing early growth phenotypes
Impact 20372150 23449627 22885924 22484627 22504419 21515849
Start Year 2008
 
Description GEFOS Consortium 
Organisation Erasmus University Medical Center
Department Department of Internal Medicine
Country Netherlands 
Sector Academic/University 
PI Contribution Provision of genome-wide association results for bone related traits. Coordination of meta-analyses.
Collaborator Contribution Provision of genome-wide association results for bone related traits. Coordination of meta-analyses.
Impact 24014423 23437003 23396134 23074152 22792071 22792070 22504420 21533022 21124946 20534768 19181680
Start Year 2011
 
Description Genetics of Obesity in Young Adults 
Organisation Danish Ministry of Health
Department Danish National Birth Cohort
Country Denmark 
Sector Public 
PI Contribution Analysis of genome-wide association data
Collaborator Contribution Availability of data in Danish cohort to analyze
Impact 21935397 22197932 23563607
Start Year 2008
 
Description Genome-wide prediction of individual risk 
Organisation University of Queensland
Department Queensland Institute of Medical Research
Country Australia 
Sector Academic/University 
PI Contribution Intellectual contribution to designing genome-wide risk scores for prediction of individual risk of disease
Impact 19553258
Start Year 2008
 
Description SpiroMeta Consortium 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of genome-wide association data
Collaborator Contribution Identification of loci affecting lung function
Impact 20010834 21946350 21625484
Start Year 2008
 
Description The Australo-Anglo-American Ankylosing Spondylitis Consortium 
Organisation University of Texas
Country United States 
Sector Academic/University 
PI Contribution Analysis of genome-wide data; Development of Diagnostic Test instrument
Collaborator Contribution Provision of genome-wide association data on Ankylosing Spondylitis cases
Impact PMID: 20062062 PMID: 21743469 PMID: 21123336 PMID: 20953190 PMID: 23749187 PMID: 22231927
Start Year 2008