Genomics of Diabetes: Functional characterisation of T2D GWAS
Diabetes already affects 415 million people worldwide. In the UK, there will be 5M people with type 2 diabetes (T2D) by 2025, accounting for 1 in 30 prescriptions and £25 billion in annual NHS costs. The focus of the Gloyn group is the translation of genetic association signals for type 2 diabetes and glycaemic traits into mechanisms for beta‐cell dysfunction and diabetes.
The over-arching aim of the group’s research is to identify effective therapeutic targets for type 2 diabetes (T2D) treatment through mechanistic studies of proteins causally implicated in T2D risk through human genetics. We have a particular focus on improving understanding of pancreatic islet cell dysfunction in type 2 diabetes. The pancreatic islet is the key tissue relevant to T2D pathogenesis, but data from human islets has not featured in major community projects in tissue genomics (GTEx, ENCODE, Epigenome RoadMap). To support the group’s efforts (and those of the wider community) to derive biological inference from T2D‐GWAS and sequencing studies, we have invested heavily in generating key data human islet transcriptome and regulome data sets.
We work both at genome-scale and at targeted loci to unlock the effector transcripts at genome wide association study (GWAS) loci using state of the art genomic techniques (including CRISPR-cas9 genome editing) in recently developed human pancreatic beta-cell models to understand what these proteins do, how they contribute to defects in insulin secretion, what networks they are involved in and how we can leverage this new knowledge to identify therapeutic targets.
We use genome editing combined with induced pluripotent stem-cells to study the impact of T2D-associated genetic variants on islet cell development and function. We are also funded to investigate the impact of T2D risk variants on pancreatic beta-cell function in vivo. We are able to recruit individuals with specific genotypes from the Oxford BioBank for detailed physiological investigations that we perform in the Oxford NIHR BRC funded Diabetes & Metabolism Clinical Research Unit in OCDEM. These studies allow us to study the impact of T2D-risk variants on beta-cell dysfunction in humans.
There are opportunities for joint projects between the McCarthy and Gloyn groups which combine statistical and computational discovery in large “omic” datasets with “wet‐lab” validation depending on the interests and experience of the student concerned. We also offer projects focused on deciphering molecular mechanisms for diabetes through the study of specific genes identified through our T2D genetic discovery efforts. DPhil projects are developed with the student and tailored to the student’s particular training and scientific interests.
Project areas: diabetes, endocrinology & metabolism and genes, genetics, epigenetics & genomics, genome-editing, human IPSC differentiation, beta‐cell dysfunction, insulin secretion. E.g. Leveraging T2D GWAS using diabetes relevant cell type specific protein-protein interaction networks; identification of causal mechanisms for beta-cell dysfunction in type 2 diabetes through genome editing of human IPS cells; genome-wide and pooled CRISPR screens for diabetes relevant cellular phenotypes
In addition to training offered within the team since we are part of the Wellcome Centre for Human Genetics team members also benefit from opportunities for training in genomic data analysis offered through the WCHG. Our large team of experienced post-doctoral fellows, research assistants and technicians also provides ample support for one-to-one training in specific laboratory techniques. Attendance at scientific meetings and presentation of data is strongly encouraged.
As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.
The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.
Our main deadline for applications for funded places has now passed. Supervisors may still be able to consider applications from students who have alternative means of funding (for example, charitable funding, clinical fellows or applicants with funding from a foreign government or equivalent). Prospective applicants are strongly advised to contact their prospective supervisor in advance of making an application.
Please note that any applications received after the main funding deadline will not be assessed until all applications that were received by the deadline have been processed. This may affect supervisor availability.
Thomsen et al Nature Genetics 2018
Mahajan et al Nature Genetics in press bioRxiv 245506; doi: https://doi.org/10.1101/245506
Thurner et al ELife 2018
Thomsen et al Diabetes 2016
Manning et al Diabetes 2017
Van de Bunt PLoS Genetics 2015
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