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Scientific summary and further information
Arthritis Research UK PhD Studentship: Functional characterisation of regulatory
genetic variants associated with ankylosing spondylitis
Lead supervisor: Dr Julian Knight, Wellcome Trust Centre for Human Genetics, Nuffield
Department of Medicine, University of Oxford
Background. Ankylosing spondylitis (AS) is a common severe inflammatory arthritis whose
pathogenesis remains unresolved. The disease is highly heritable and shows a strong
genetic association with the Major Histocompatibility Complex (MHC), in particular HLA-B27.
However only a minority of individuals carrying HLA-B27 develop AS and recent genomewide association studies (GWAS) have identified at least 14 other AS associated genomic
loci. The majority of non-MHC associations are with genetic markers (single nucleotide
polymorphisms, SNPs) in intergenic regions, raising fundamental questions about what the
specific causal functional variants are, which genes they modulate expression of, and how
this is relevant to disease.
Expression quantitative trait (eQTL) mapping provides a complimentary and informative
approach to GWAS by defining genetic variants associated with differential gene expression
at genome-wide resolution. We have recently performed an extensive eQTL analysis for
primary immune cells from healthy volunteers that revealed how a number of SNPs
associated with AS were also associated with differences in gene expression. This provides
a new route-map of putative regulatory variants and loci relevant to disease. The work will
be further facilitated by establishment of the GenExpressID study (Genetics of Gene
Expression in Immune-related Disease, www.genexpressID.org) recruiting patients with AS
and isolating specific immune cell populations for functional genomic analysis.
Objectives of studentship. The overall aim is to understand the functional basis for
observed genetic associations with AS by identifying causal functional alleles, their
mechanism of action and modulated genes. Specific objectives are: (1) To validate and fine
map regulatory variants associated with AS; (2) To use data from functional genomic and
epigenomic profiling to generate hypotheses regarding mechanism of action for regulatory
variants; (3) To functionally characterise specific candidate loci in AS including variants
modulating the aminopeptidase genes ERAP1 and ERAP2, the transcription factor ETS2,
ANTXR2 and a gene cluster at chromosome 9q34.
Approach. The work to be undertaken during this studentship would involve wet lab
functional genomic approaches and in silico bioinformatic analysis. The host lab has
significant expertise in required approaches together with access to necessary resources
and samples. The student would quantify gene expression at the gene and allele-specific
level together with assaying chromatin state and protein-DNA interactions, gene function
and assays specific to hypotheses being tested. As part of a broader initiative within the host
lab, the student would be involved with, and have access to, global transcript and chromatin
profiling based on high throughput sequencing led by experienced postdoctoral scientists.
The project is ambitious but achievable given the high level of support available and being
part of an extensive programme in functional genomics and immune-related disease in the
host lab.
Predicted outcome/wider impact of research. This project would provide new insights into
risk factors for disease development in AS, the disease processes responsible for AS,
potential biomarkers and novel drug targets.
Training/facilities. The project would provide an outstanding training opportunity. The
student would gain expertise in wet lab molecular genetic techniques, cutting-edge genomic
technologies that take advantage of high throughput sequencing, and current bioinformatic
and statistical genetic analysis. The student would be working as part of an integrated team
and benefit from day to day supervision from senior postdocs within the group and
established collaborations. The studentship is based at the Wellcome Trust Centre for
Human Genetics, an established international centre of scientific excellence in complex
disease genetics with very strong translational links with clinical rheumatology and related
institutes including the Botnar Research Institute and Kennedy Institute of Rheumatology.
There is an exceptional teaching and research environment at the University of Oxford with
access to training programmes in Genomics and Statistics and the Skills Training
Programme of the Medical Sciences Doctoral Training Centre. The student would have a
nominated mentor and be a member of a College at the University of Oxford. The host
institute is an established international centre of scientific excellence in complex disease
genetics with outstanding facilities and expertise for functional genomics and highthroughput sequencing, ensuring the feasibility of the proposed work.
Web resources
GenExpressID study www.genexpressID.org
Knight lab website www.well.ox.ac.uk/knight-j
References and further reading
Brown MA. 2011 Progress in the genetics of ankylosing spondylitis. Briefings in Functional
Genomics 10, 249-57.
Evans DM et al. 2011 Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis
implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility. Nature
Genetics 43, 761-7.
Fairfax BP, Makino S, Radhakrishnan J, Plant K, Leslie S, Dilthey A, Ellis P, Langford C,
Vannberg FO, Knight JC. 2012 Genetics of gene expression in primary immune cells
identifies cell-specific master regulators and roles of HLA alleles. Nature Genetics 44, 502510
Knight JC. 2012 Resolving the variable genome and epigenome in human disease. Journal
of Internal Medicine 271, 379-91.
Knight JC. 2009 Human Genetic Diversity. Functional Consequences for Health and Disease.
Oxford, Oxford University Press.
Reveille JD et al. 2010 Genome-wide association study of ankylosing spondylitis identifies
non-MHC susceptibility loci. Nature Genetics 42, 123-7.
Reveille JD. 2012 Genetics of spondyloarthritis--beyond the MHC. Nature Reviews
Rheumatology 8, 296-304.
Vandiedonck C, Taylor MS, Lockstone H, Plant K, Taylor JM, Durrant C, Brockholme J,
Fairfax BP, Knight JC. 2011 Pervasive haplotypic variation in the spliceo-transcriptome of the
human Major Histocompatibility Complex. Genome Research 21, 1042-54.