Restless Legs Syndrome: investigating the physiological pathways associated with RLS
Restless Legs Syndrome (RLS) is defined as the painful urge to move ones legs, relieved by movement and worse in the evenings. In this project, you will define the demographic, genetic, metabolic factors associated with RLS and aim to describe the physiological pathways associated with RLS.
Restless Legs Syndrome is common in European populations, with a reported prevalence of approximately 10% in many studies. The severity varies, but a quarter of these patients will seek help from their physician. RLS can be defined by a simple questionnaire that differentiates between RLS, cramp or other movement disorders, although the gold standard includes face-to-face interviews, clinical examination to include comorbidities that may cause pain in the legs. Objective measurement of RLS can be obtained by neurophysiological studies and the severity of the syndrome can be delineated by specific questionnaires.
The pathological basis of Restless Legs disorder has not been fully defined, but has been associated with reduction in signalling in striatal dopaminergic pathways and our own genetic analysis also suggests a fundamental disturbance or modulation of circadian rhythm. Restless Legs Syndrome has also been associated with a minority of patients with iron deficiency. RLS can be treated not only by dopaminergic agents, but also by IV iron replacement in those who are iron deficient.
We now have the opportunity to study the clinical epidemiology of Restless Legs Syndrome and its association with genetic traits and disorders of iron metabolism in both intrinsic and recent onset RLS in our cohort of 50,000 donors who have participated in the INTERVAL trial exposed to different frequencies of blood donation and therefore different rates of iron deficiency (de Angelantonio et al, 2017). We are completing a new GWAS of iron metabolism including the effects of genetic traits on the ability to give blood frequently and levels of ferritin and hepcidin (Astle et al, 2016; Raymond et al., in preparation).
We have used the results of this trial and extended genotypic analyses from all participants to complete a GWAS of restless legs syndrome (Schormair et al, 2017). We identified and replicated 19 risk loci and confirm MEIS1 as the strongest genetic risk factor. The loci highlight molecules linked to axon guidance (SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster, MYT1), and corroborate an important role of neurodevelopmental processes in RLS pathogenesis. Loci containing the genes of thalidomide-binding ubiquitin ligase substrate receptor CRBN and its physiological substrate MEIS2 suggest completely new avenues for treating the disease. This meta-analysis has therefore increased the number of new candidate loci associated with restless legs syndrome over three-fold to 19 and provided new pathways for future functional analysis.
In this project, we will examine the long term outcome of RLS as defined by quality of life surveys and hospital morbidity surveys and by detailed neurophysiological follow-up in patients with specific genotypes and in iron deficiency associated with RLS. We will examine how the genotypes and biochemical or iron phenotypes are associated with the natural history of RLS and outcome of treatment of RLS with dopaminergic agents and/or IV iron replacement. Finally, we will explore how the novel genetic pathways associated with RLS may help to define novel therapies for this painful affliction.
Students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
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 support the careers of female students and staff.
Astle et al., (2016) The allelic landscape of human blood cell trait variation and links to common complex disease, Cell, 167, 1415–1429.
Di Angelantonio E, Thompson SG, Kaptoge S, Moore C, Walker M, Armitage J, Ouwehand WH, Roberts DJ*, Danesh J*; INTERVAL Trial Group. (2017) Efficiency and safety of varying the frequency of whole blood donation (INTERVAL): a randomised trial of 45 000 donors. Lancet, Sep 20. pii: S0140-6736(17)31928-1.
Schormair S et al., (2017) Meta-analysis of > 100,000 individuals of European ancestry identifies 19 genome-wide significant risk loci for restless legs syndrome. Lancet Neurol, 16, 898-907.