6. Understanding Endometriosis, Uterine Fibroids and Associated Symptoms through Large-scale Genomic Epidemiological Approaches
This outline describes our genomic epidemiological research programme within the Endometriosis CaRe centre (Nuffield Dept of Obstetrics & Gynaecology) and the Wellcome Trust Centre for Human Genetics, and opportunities for DPhil/MSc projects therein.
Understanding Endometriosis, Uterine Fibroids and Associated Symptoms through Large-scale Genomic Epidemiological Approaches
This outline describes our genomic epidemiological research programme within the Endometriosis CaRe centre (Nuffield Dept of Obstetrics & Gynaecology) and the Wellcome Trust Centre for Human Genetics, and opportunities for DPhil/MSc projects therein. The programme connects directly with laboratory-based and clinical translational programmes offered within the Endometriosis CaRe centre.
We focus on understanding the pathogenesis of endometriosis, uterine fibroids and related women’s health conditions through the integration of large-scale genomic, molecular and environmental epidemiological approaches. Endometriosis is a common chronic inflammatory disease, characterised by the presence of tissue that resembles endometrium (the lining of the uterus) outside the uterus. It causes pelvic pain and reduced fertility in an estimated 176 million women worldwide. Definitive diagnosis requires surgery and is often delayed for years.
Current treatments are limited to surgical removal of lesions, with high recurrence rates, and/or hormonal drugs with many side effects. The causes of endometriosis are largely unknown, but heritability has been estimated at ~50%. Uterine fibroids (leiomyomata) are common benign excessive growth of the myometrium, the causes of which are similarly poorly understood. Symptomatology partly overlaps with endometriosis, featuring heavy menstrual bleeding and pelvic pain, and heritability estimates are similar. We have led the discovery of the majority of genetic variants associated with endometriosis to date through genome-wide association studies with international collaborators (Nature Genetics, 2011; Nature Genetics, 2012; Human Reproduction Update, 2014). The results have challenged prior-held aetiologic hypotheses, provided the first evidence of shared effects of variants with metabolic phenotypes, and demonstrated genetic differences in disease origins that has direct implications for existing disease classifications. These genetic variants explain only a fraction of heritability, so we are planning further work to identify other associated common and rare variants using new datasets, including – for example – the UK Biobank. We are particularly interested in leveraging the wealth of data in the UK Biobank (clinical, genomic and brain imaging data) for the investigation of endometriosis and its shared basis with pain susceptibility and comorbidities. Similarly, we are conducting discovery analyses for genetic loci underlying uterine fibroids, and investigating overlap with endometriosis. In addition to human genomics, we previously identified familial aggregation of spontaneous endometriosis in rhesus macaques (RM) with collaborators in the US, and are studying RM pedigrees for comparative analyses.
In addition to genomic discovery analyses, we are working on understanding the effects of implicated genetic variants on biological pathways through analysis of e.g. transcriptomic (RNAseq) and DNA methylation data from tissues and cell types relevant to endometriosis and uterine fibroids (endometrium, endometriotic and uterine fibroid disease, fat) from women undergoing laparoscopy, recruited in our ongoing ENDOX study. We lead an international programme that produced standardised clinical and epidemiological data collection and standard operation procedures for sample collection, which will enable further large-scale collaborations in the field (endometriosisfoundation.org/ephect).
There are a number of potential DPhil projects available within the group, which would be tailored to a candidate’s preferences. These can include:
• Identifying pain mechanisms in endometriosis through analysis of clinical, genomic and brain imaging data from the UK Biobank;
• Understanding the effects of identified genetic variants on (dis)regulation of transcription in endometriosis, endometrium and its constituent cell types;
• Identifying common biological mechanisms underlying endometriosis and comorbidities;
• Leveraging ‘omics’ data to identify sub-types of endometriosis;
• Comparing the genetic aetiology of endometriosis between humans and the rhesus macaque.
We are a multi-disciplinary, dynamic group based at both the Endometriosis CaRe Centre (Nuffield Dept of Obstetrics & Gynaecology) and the Wellcome Trust Centre for Human Genetics (WTCHG) with strong links to other centres locally (e.g. the Oxford Centre for Functional MRI of the Brain, FMRIB). Students will benefit from an exciting combination of clinical and basic research environments offered by both. The Endometriosis CaRe centre focuses on the integration of clinical diagnosis, care and treatment of the disease with clinical and basic research. At WTCHG, we are part of the Genetic and Genomic Epidemiology Unit (GGEU), also comprising the Morris (statistical genetics) and Lindgren (genomics of obesity-related traits) groups. Students will be strongly encouraged to publish their work, present at international conferences, attend bi-weekly GGEU meetings, journal clubs, as well as departmental seminars and training courses.
Depending on the project, you will get extensive opportunity to gain knowledge and experience of state-of the-art computational, statistical, and technological methodologies for the generation and analysis of large-scale genomic data, such as genotyping microarray/sequencing, mRNAseq and miRNAseq, (a particular strength of WTCHG), and/or MRI brain imaging data.
The group benefits from a strong international network of collaborators in the fields of endometriosis, statistical genetics, genomics, bioinformatics, and functional biology locally, with whom students will be able to collaborate (e.g. Harvard Medical School, Boston,US; University of Michigan, Grand Rapids, US; Queensland Institute of Technology, Brisbane, Australia; Baylor College of Medicine, Houston, USA; University of Madison-Wisconsin, Madison, US; University of Tartu, Estonia).
We invite both funded and unfunded applicants, though we currently do not have funded DPhil projects in place. For eligible applicants without secured funding we are happy to advise on the potential (competitive) scholarship routes available.