MRC-GSK pilot programme to identify new targets and biomarkers from genetic association studies

Lead Research Organisation: Medical Research Council
Department Name: Medical Research Council

Abstract

The rising prevalence of obesity and related metabolic diseases is a major public health problem requiring a broad spectrum of approaches to enhanced prevention and treatment. One element of this is the generation of greater understanding about how our genetic make up and lifestyles interact to bring about these disorders. Previously progress in this area had been limited by our approaches to trying to understand the genetic basis of common disorders like obesity and type 2 diabetes. However, recently it has become possible beyond the former approach of studying the association with disease of single gene variants identified on the basis of prior knowledge of possible biological pathways. New approaches based on studying many hundreds of thousands of variants at once have become possible because of technological advances following the human genome project. However, the downside of this increase in the scale of genetic information is that studies have had to involve many more participants since the chance of an association being found simply by chance is considerable if studies are too small. Therefore, in this study, we will create a collaborative network between research groups to combine existing genetic data from large population-based cohort studies in order to study the genetic basis of 5 common metabolic traits. Following this initial analytical stage, we will confirm the findings in other large studies to reduce the possibility of false discovery and then undertake further work to pinpoint exactly where in the genome the genetic signal is coming from. In this way, we will contribute to discovering new variants underlying the distribution of these common metabolic traits which in turn will contribute to the development of novel preventive and therapeutic strategies.

Technical Summary

The public health importance of obesity and related disorders is unquestionable and improved understanding of the molecular basis of these disorders is an important part of a broader strategic approach to enhanced prevention and treatment. Recent studies have shown that genome-wide association (GWA) studies are an effective strategy for identifying novel genetic risk factors for complex diseases. GWA studies of quantitative traits provides a powerful research framework to examine the aetiology of metabolic disease, providing greater statistical resolution than the assessment of discrete traits for equivalent sample sizes. However, because genetic variants are likely to only explain a very small proportion of the variation in a biomarker trait or risk factor, the identification of reliable statistical associations requires large samples sizes. In this project we will bring together existing genome-wide association data from two population based cohorts (EPIC and Lausanne), in order to create an initial starting point for the analysis of quantitative metabolic traits. We will undertake a meta-analysis of GWA studies for five trait areas; obesity traits, lipids, blood pressure, glucose and insulin and age at menarche. Additional phenotypic areas will be considered at a later date, but we will consolidate our initial efforts on these five areas. Using a network of population-based cohort studies, we will undertake large scale replication of initial positive associations in order to select loci to take forward to a third stage of detailed refinement of the source of the association signal. Finally we will examine the association between confirmed loci and intermediate biomarkers that are more proximal on the putative causal pathway. This stage will necessitate the selection and measurement in specific cohorts of informative biomarkers. In turn, this will feed into the design of new analyses of GWA data and separately to studies of the function of the newly identified variants.

Publications


10 25 50


publication icon
Böger CA (2011) CUBN is a gene locus for albuminuria. in Journal of the American Society of Nephrology : JASN



publication icon
Coronary Artery Disease Consortium (2009) Large scale association analysis of novel genetic loci for coronary artery disease. in Arteriosclerosis, thrombosis, and vascular biology





 
Description MAGIC consortium 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution We were part of the group that formed the MAGIC consortium which is designed to examine the genetic determinants of glucose and insulin traits.
Collaborator Contribution Multiple cohort studies with glucose and insulin measurement and GWAS data.
Impact Multiple papers on the genetic determinants of glucose and insulin related traits.
Start Year 2008
 
Description MRC-GSK consortium 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution This grant application was funded under a special programme between MRC and GSK. The work involves members of our Unit plus colleagues from GSK in Philadelphia (Drs Mooser, Ehm and Waterworth), CHUV in Lausanne (Professor Vollenweider and Waeber) and the WT Sanger Institute (Barosso).
Collaborator Contribution Joint analyses and publications.Joint analysis of data including the Lausanne Study and joint publications.Joint analyses and publications.
Impact All the publications listed as emerging from this grant are a result of this collaboration. The outputs and deliverables from this milestone driven project have been reported to the MRC-GSK oversight committee in September 2010.
Start Year 2007
 
Description MRC-GSK consortium 
Organisation Lausanne University Hospital (CHUV)
Country Switzerland, Swiss Confederation 
Sector Hospitals 
PI Contribution This grant application was funded under a special programme between MRC and GSK. The work involves members of our Unit plus colleagues from GSK in Philadelphia (Drs Mooser, Ehm and Waterworth), CHUV in Lausanne (Professor Vollenweider and Waeber) and the WT Sanger Institute (Barosso).
Collaborator Contribution Joint analyses and publications.Joint analysis of data including the Lausanne Study and joint publications.Joint analyses and publications.
Impact All the publications listed as emerging from this grant are a result of this collaboration. The outputs and deliverables from this milestone driven project have been reported to the MRC-GSK oversight committee in September 2010.
Start Year 2007
 
Description MRC-GSK consortium 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom of Great Britain & Northern Ireland (UK) 
Sector Charity/Non Profit 
PI Contribution This grant application was funded under a special programme between MRC and GSK. The work involves members of our Unit plus colleagues from GSK in Philadelphia (Drs Mooser, Ehm and Waterworth), CHUV in Lausanne (Professor Vollenweider and Waeber) and the WT Sanger Institute (Barosso).
Collaborator Contribution Joint analyses and publications.Joint analysis of data including the Lausanne Study and joint publications.Joint analyses and publications.
Impact All the publications listed as emerging from this grant are a result of this collaboration. The outputs and deliverables from this milestone driven project have been reported to the MRC-GSK oversight committee in September 2010.
Start Year 2007
 
Description Press coverage 
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 Press reports of papers describing genetic basis of common disease.

Considerable press interest in findings of genetic basis of common disease.
Year(s) Of Engagement Activity 2009,2010