Our Research

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.

A taste of what we are doing…

Whole-genome sequencing study of IBD

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.

Multi-omics at a population scale

Our clinical collaborations up and down the United Kingdom allow us to collect material (blood and gut samples) for high throughput multi-omic assays. We currently perform both scRNA and scATAC sequencing on samples from hundreds of individuals to derive population level insights into age, sex and disease-level differences. We combine these data with genotype information to map quantitative trait loci that inform our understanding of the mechanisms of disease.

Identifying novel drug targets for immune-mediated diseases

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.

Genetic regulators of vaccination response

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.