The genetic susceptibility loci for complex disorders such as multiple sclerosis (MS) rarely encode protein. A better understanding of the intracellular mechanisms by which MS genetic susceptibility variants function is crucial to the development of more effective targeted treatments. Growing evidence suggests that these loci confer risk by controlling gene expression in specific disease-relevant cells by altering regulatory genetic sequences. This can be explored by correlating genotype at susceptibility loci with expression of nearby genes (cis-regulation), with greatest sensitivity demonstrated in the most relevant cell types.Aims
1. Interrogate MS susceptibility loci for cis-regulatory effects. 2. Establish a publicly available resource of genome-wide RNA sequencing expression data in CSF-derived CD4 +T cells. 3. Correlate gene expression data with detailed longitudinal clinical data to seek biomarkers of prognosis. This study will provide fresh insights into MS disease mechanisms and have relevance across all complex diseases by better defining relationships between susceptibility variants and gene expression. Identifying novel pathological cellular pathways may provide potential therapeutic targets, and detecting gene expression profiles that predict disease severity could help identify patients requiring early treatment. This work will be completed thanks to the ABN and Guarators of Brain Fellowship award I obtained in 2016.