Although genome wide association studies (GWAS) have been used with great effect to detect variants associated with many diseases, they generally do not pinpoint the causal gene or causal variant since they are unable to distinguish between highly correlated markers. Functional studies are required to identify causal disease markers and to move forward in the post-GWAS era by addressing the question of how genetic variation affects gene function and, in turn, how this relates to the molecular mechanism for the phenotype. Indeed, the majority of lead GWAS genetic variants map outside gene regions, with more than half residing a significant distance from the nearest gene. In order to progress these findings towards novel drug discovery, patient stratification and ultimately cure, it is necessary to determine the genes implicated by GWAS findings.
The disease associated variants that map outside gene regions are likely to act by influencing gene regulation. This long-distance regulation is thought to act through physical contact with target genes. We use chromosome conformation capture techniques to interrogate all known GWAS associated regions for rheumatoid arthritis (RA), to detect long range physical interactions and thus determine the genes regulated by RA associated variants. This approach has the advantage of potentially highlighting causal variants in regions where genetic analysis does not have the sensitivity to distinguish between a number of highly correlated association signals. Subsequently, the functional characterization of disease associated regulatory elements helps us understand how genetic variation contributes to disease risk.
We also perform integrative analysis of “omics” data, such as gene expression and epigenetic marks, which can help us understand the biology behind disease and suggest novel therapeutic targets.
The identification of causal genes and potential regulatory mechanisms for each GWAS associated region will be a significant step forward for RA.
The aims of the programme of work are:
- To identify the disease genes at all RA susceptibility loci detected in GWAS.
- To refine the associated regions, and highlight likely causal variants, in loci with large, genetically intractable associations.
- To characterize regulatory elements and causal mechanisms by which genetic variation contributes to phenotype.
- To elucidate disease pathways which potentially aid the discovery of novel targets for pharmacological therapy for RA.
- DNA and RNA sequencing
- Gene expression analysis using microarrays and quantitative PCR
- Chromosome conformation capture and Hi-C
- Chromatin immunoprecipitation
|Professor Peter Fraser||Babraham College, Cambridge, UK|
|Professor Magnus Rattray||University of Manchester, UK|
|Dr Caroline Ospelt||University of Zurich, Switzerland|
|Professor Souyma Raychaudhuri||
Broad Institute of Harvard and Massachusetts Institute of Technology, USA
- The vast majority of genetic associations to complex musculoskeletal disease, such as RA, JIA and PsA, lay outside traditional annotated gene regions
- Accumulating evidence suggests these variants influence gene regulation in specific cell types, at specific developmental stages and when placed under different environmental stress
- Experiments initiated in our laboratory will determine the genes regulated by our genetic findings, in the relevant cell types and stimulatory conditions to disease
- Preliminary work from our laboratory suggests many associated variants may influence the regulation of genes a long distance from the lead association signal.