Our lab is broadly interested in understanding how genetic variation contributes to human disease. We work in two biologically very different disease areas to give us multiple angles on these questions.

Inflammatory bowel disease (IBD)

enrich
Translating GWAS into new drug targets
After a decade of GWAS success, the group is now focused on turning those discoveries into valuable leads for new drug targets. Our main disease focus is IBD, where we are working on both computational analyses of genetic data and high throughput functional screens to better understand causal variants, genes and mechanisms implicated by GWAS. Much of this work is done in collaboration with Open Targets, which Jeff also leads.
low coverage sequencing
Whole-genome sequencing
To complement our ongoing follow-up of IBD GWAS results, and building on our previous work with low-coverage genome sequencing, we are generating deep whole-genome sequences to identify rare coding and non-coding risk variants. Over the next few years we plan to sequence up to 20,000 IBD patients, and analyse them with 50,000 sequenced controls.
People: Alex Sazonovs, Dan Rice
low coverage sequencing
Genetic determinants of drug response
Anti-TNF therapy is one of the most important treatments for IBD, but many patients either do not respond at all, or lose response over time. Together with colleagues around the UK we are analysing the PANTS cohort to identify genetic determinants of response to anti-TNF treatment in the hope of better using the drugs we already have to treat IBD and other inflammatory disorders.
People: Alex Sazonovs
low coverage sequencing
Exploring the role of genetics and the microbiome in progression
For some IBD patients their disease will respond well to early treatment, and enter long periods of remission. For others, however, disease “flares” will frequently occur, disrupting their lives, requiring increased treatment, and even surgery or hospitalisation. At present it is difficult to determine in advance which patients will flare, or when this will occur. Together with the PREDICCT study we are working to understand how both genetic background and gut microbiome are involved in this key disease process.

Severe neurodevelopmental disorders

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Recessive analyses in the Deciphering Developmental Disorders (DDD) study
DDD is a collaborative project involving WTSI and the 23 National Health Service Regional Clinical Genetics Services in the UK. We have previously published a number of discoveries primarily driven by studying de novo damaging mutations found in affected children but not their parents. More recently we have moved on to searching for recessive coding causes in DDD, with a particular focus on constructing statistically robust methods to discover new genes given background population frequencies.
People: Hilary Martin, Wendy Jones
External site: www.ddduk.org
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Common variant contribution to DDD
Another area of interest within DDD is to look for contributions to these disorders, which are typically thought to be purely monogenic, from common variation (i.e. GWAS). It’s not yet clear how rare and common variation combine in these severe disorders, but there is increasing evidence that essentially all genetic traits and disorders have some complexity.
People: Mari Niemi, Hilary Martin