Kennedy Trust Prize Studentships
Decoding the genetic architecture of inflammatory arthritis at the single-cell level
- Project No: KTPS-RACE-2
- Intake: 2021 RACE
Genome-wide association studies (GWAS) have revealed hundreds of genetic variants linked to different forms of inflammatory arthritis. The cell types in which these variants act to promote disease remain, however, mostly unknown. Recently, exciting breakthroughs in single-cell genomics have made it possible to build exquisitely detailed maps of cellular heterogeneity in both health and disease. In this project, the DPhil student will integrate information from such single-cell atlases with findings from GWAS studies to help pin-point cells with a causative role in pathogenesis. The research will involve a comparative analysis of different types of arthritis to discover disease-specific inflammatory responses. The main contrast will be between rheumatoid arthritis (RA) and ankylosing spondylitis (AS) using single-cell human tissue datasets from the NIH AMP project (RA) and the Sansom/Bowness groups (AS). These two forms of inflammatory arthritis have different genetic associations and largely distinct clinical presentations. The project will also make use of spatial data and cellular maps of healthy joints which we are currently generating as part of the Human Cell Atlas project (https://www.humancellatlas.org/).
Specifically, in the project the student will:
(1) Multi-modal single cell datasets from AS, RA and healthy human joints will be gathered and analyzed using a common computational workflow (already established; https://www.github.com/sansomlab/tenx) to generate a comparative atlas.
(2) Using algorithms developed by the Jostins group (and others, such as e.g. EWCE and MAGMA) the enrichment of AS and RA GWAS hits will be assessed across the single-cell cell atlases.
(3) The cell types found to be enriched for genetic associations will be carefully compared (e.g. in abundance, phenotype) between the diseases to identify candidate pathogenic cells, pathways and genes in both AS and RA.
(4) Candidate cells, pathways and genes will be validated (e.g. using the BD Rhapsody system and/or multimodal 10X analysis) and studied (e.g. spatially by confocal or with the Cell DIVE platform for multiplexed image analysis) using tissue from AS cohorts in Oxford (Prof Bowness) and RA cohorts in Birmingham (Prof Karim Raza)
- Progress in our understanding of the pathogenesis of ankylosing spondylitis. Simone D, Al Mossawi and Bowness P. Rheumatology (Oxford), 2018
- New pathogenic insights into rheumatoid arthritis. Gurpreet Jutley, Karim Raza & Christopher Buckley. Current Opinion in Rheumatology, 2015
- Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci. David Ellinghaus, et. al. Nature Genetics, 2016
- Distinct fibroblast subsets drive inflammation and damage in arthritis. Adam P. Croft, et. al. Nature, 2019
Stephen Sansom, Kennedy Institute, University of Oxford