The immune-system must maintain a delicate balance; it should be sensitive enough to eliminate invading pathogens while being tolerant of the body's own cells. Autoimmune diseases can occur when the immune-system gets this balance wrong and attacks cells and substances typically found in the body. Autoimmune diseases are known to "run in families", suggesting that inherited genetic risk may play a central role in susceptibility. The aim of our research is to improve our understanding of autoimmunity by identifying and functionally characterizing the specific regions of the genome that influence disease risk.
We use high-throughput genome-wide genetic screens to identify regions of the human genome that are associated with immune-mediated diseases (chiefly, primary sclerosing cholangitis and inflammatory bowel disease). This ‘hypothesis-free’ approach enables us to identify novel aspects of disease biology (e.g autophagy in IBD). We identify disease relevant genes and cell types by combining genetic association data with gene-regulatory data we, and others, have generated across disease relevant cell types. We then move to the wet lab where we use a variety of cellular assays to understand how particular genetic variants influence cell function to influence disease susceptibility.
We are whole-genome sequencing ~10,000 IBD cases and ~15,000 population controls to probe the entire allelic spectrum for association to IBD. We are sequencing at 15X depth to enable us to identify >90% of singletons present in a genome. The majority of cases and controls are consented for genotype/phenotype-based recall so we can investigate the functional consequences of associated variants at a cellular level.
We are combining GWAS data with molecular and cellular QTLs to identify the role of non-coding variation to (dys)regulation of genes associated with immune-mediated disease. We undertake statistical fine-mapping of the association statistics in an attempt to identify causal variants. We then head to the wet lab to identify the cellular functions perturbed by these variants in disease relevant cell types. We have large ongoing projects in this area for both IBD and PSC.
The aim of this project is to better understanding how regions of the genome associated with risk for IBD (by the computational arm of the lab) affect cell function. We are using CRISPR-Cas9 to modify the genomes of cells of relevance to IBD e.g. immune and intestinal cells, followed by cell phenotyping. This approach will allow us to determine the direct effect of many disease risk variants and potentially, to identify new therapeutic disease targets and/or pathways.
To better understand how genetic variants influence immune-mediated diseases we must better understand their role in the healthy immune response. To this end, we are undertaking several systems vaccinology studies where cohorts of healthy individuals are profiled (gene-expression, serology etc) before and after vaccination. We then look to identify the role that genetic variation plays in shaping vaccination response.