Fine mapping multiple sclerosis
EBPOD 2017: Project 9
This is one of 11 joint postdoctoral fellowships offered by EMBL-EBI, the NIHR Cambridge Biomedical Research Centre and the University of Cambridge’s School of the Biological Sciences in 2017.
Multiple sclerosis is a common cause of chronic neurological disability and a major drain on the health economy of the United Kingdom. Genomewide Association Studies (GWAS) have been spectacularly successful at identifying susceptibility loci for the disease but little knowledge regarding the aberrant biology underlying the development of this devastating disease has yet emerged from these efforts. The associated variants overwhelmingly map to regulatory regions of the genome that are active in immune cells, but extensive linkage disequilibrium and a lack of relevant epigenetic annotation has confounded efforts to translate these discoveries into meaningful insights. This project will overcome these barriers by leveraging the enormous power of the 500,000 genotyped individuals in the UK Biobank, coupled with genotypes from over 10,000 cases and disease specific epigenetic data. These data will enable fine mapping of associated loci to unprecedented resolution and thereby identify mechanisms of disease which will in turn transform the prospects for the development of rational therapy. We believe that the emergence of these powerful resources offer a unique opportunity to radically advance our understanding of the aetiology of multiple sclerosis.
The project will use Bayesian methods to integrate these novel data sets, which we estimate will provide power to identify manageably sized credible sets of potentially causal variants for more than half of the 200 GWAS loci identified to date. The project will also utilize the extensive overlap in genetic architecture that is known to exist between autoimmune diseases to boost power in the analysis of multiple sclerosis. Using colocalization methods w will establish for each associated locus which autoimmune diseases are also influenced by the multiple sclerosis risk variants so that data from these diseases can be included in the mapping efforts. The UK Biobank includes over 50,000 individuals that have some form of immune mediated inflammatory disease including almost 2,000 with multiple sclerosis. By comparing, contrasting and combining the data from these different diseases the project will establish a disease mechanism based taxonomy for these diseases which will transform the opportunities for stratified medicine and personalized therapy.
Prof Stephen Sawcer and Dr Jeff Barrett are both prominent members of the Wellcome Trust Case Controls Consortium (WTCCC) and as such have contributed to a multitude of genomewide association studies and have extensive experience in this field.
Stephen Sawcer is the Professor of Neurological Genetics at the University of Cambridge and an Honorary Consultant Neurologist at Addenbrookes Hospital. He has worked on the genetics of multiple sclerosis and other neurological conditions for over twenty years. He has coordinated the national recruitment effort in MS which has collected DNA from over 17,000 cases. Prof Sawcer is a leading member of the International Multiple Sclerosis Genetics Consortium (IMSGC).
Jeff Barrett is a faculty member at the Wellcome Trust Sanger Institute and European Bioinformatics Institute, and is a leading authority on the genetics of complex traits. Dr Barrett is a leading member of the International Inflammatory Bowel Disease Genetics Consortium (IIBDGC) and has completed GWAS in multiple disease traits. Dr Barrett has expertise in large data processing including whole genome resequencing and is the director of the “Open Targets” (http://opentargets.org); the organisation which seeks to maximise the translation of progress in complex genetics.