The Genetic Analysis of Multiple Sclerosis

Through genome-wide association studies and related follow up efforts we have identified over 100 genetic variants that influence the risk of developing multiple sclerosis. These variants map almost exclusively to regulatory regions of the genome that are active in immune cells suggesting that these variants primarily exert their effects by altering the expression of otherwise normal genes in critically important immune cell sub-types. In order to try and understand more precisely how these associated variants influence the development of multiple sclerosis we are undertaking a range of projects.

In work already completed we have established that at least two of the associated variants influence the expression of key immune signalling genes in B cell sub-types. These data confirm the importance of B cells in pathogenesis which is in keeping with the latest clinical trial data showing the positive effects of anti-B cell therapies. This project will focus on fine mapping the causal variants underlying observed associations by exploring the expression of key immune genes in B cell subtypes. The work will involve mapping of transcription and chromatin architecture, as well as protein expression and cell function.

The highly significant overlap in the genetic architecture of immune mediated inflammatory diseases (IMID) suggests that there are key pathways in the immune system that influence the propensity to autoimmunity. This project will use data from UK Biobank (500,000 genotyped individuals) to dissect out the genetic architecture of these common pathways. The project will then use genomewide methylation mapping to fine map associated variants epigenetically and determine the functional effects of these variants.

3As part of the Cambridge Single Cell Analysis Core Facility we are undertaking single cell expression profiling in cells from the cerebrospinal fluid and blood of patients and controls. This project will allow a transcriptional based taxonomy of immune cells and identify master transcriptional regulators of relevance in multiple sclerosis. The project will also explore the epigenetic signature and functional effects of identified regulators.

The successful student will work closely with colleagues at the McGill University Epigenomics Mapping which is a leading institution in the International Human Epigenome Consortium (IHEC), the project may include the opportunity for willing students to spend a period of their research in Montreal.