Population-level imaging and genetic analyses to determine how bone marrow adiposity impacts human health

Additional Supervisors: Prof Ewan Pearson (University of Dundee) & Prof Jimmy Bell (University of Westminster)

Background

Bone marrow adipose tissue (BMAT) accounts for up to 70% of total bone marrow volume and approximately 10% of total fat mass in lean, healthy humans [1]. BMAT further increases with ageing and in diverse clinical conditions, including osteoporosis, obesity, type 1 diabetes, oestrogen deficiency, radiotherapy and glucocorticoid treatment. In striking contrast to other adipose depots, BMAT also increases during caloric restriction in animals and in humans with anorexia nervosa [1-3]. Thus, BMAT is a major component of normal human anatomy; it is distinct to other types of adipose tissue; and it is altered in numerous clinical contexts.

These observations suggest that BMAT plays a role in normal physiological function and might also impact skeletal, metabolic and ageing-associated diseases. However, study of BMAT has been extremely limited, and therefore the formation and function of BMAT remains poorly understood.

Magnetic resonance imaging (MRI) is emerging as a key tool for non-invasively assessing the properties of BMAT. For example, MRI can measure both the extent of bone marrow adiposity (BMA) and the degree of saturated and unsaturated lipids within the bone marrow. This approach has been applied in a handful of smaller-scale human cohort studies, revealing some insights into BMAT’s association with human skeletal and metabolic health [4]. However, MRI-based BMAT analysis has never been done on a larger scale. Such population-level studies would have enormous potential to reveal fundamental knowledge of the formation and function of MAT, including the association with physiological, pathological and genetic variables. Such knowledge would provide new understanding about the factors that regulate BMAT development, as well as highlighting how altered BMAT content might impact human health and disease.

Aims

Determine how BMAT properties vary on a population level - The UK Biobank has begun a major study to MRI scan 100,000 participants. Data from this ongoing study will be analysed to determine the percentage of BMA and the degree of saturated and unsaturated lipids in bone marrow of each participant [4]. This will be done in two phases: firstly, manual analysis of up to 500 scans will generate a foundational dataset. Secondly, this foundational dataset will be used for initial association analyses (Aim 2) and to develop machine-learning algorithms to automate BMAT analysis of the remaining Biobank MRI scans. These approaches will establish how the key properties of BMAT vary across a large population.

Identify the physiological, pathological and genetic determinants of altered MAT - The BMAT properties established in Aim 1 will be analysed for associations with physiological (e.g. age, sex, ethnicity, hormonal status), pathological (e.g. obesity, diabetes, osteoporosis, clinical treatments) and genetic (e.g. SNPs) parameters. The latter will initially focus on SNPs known to impact bone mineral density or circulating adiponectin, two parameters implicated with altered MAT. These associations will first be assessed using the foundational scanning dataset of 1,000 individuals (Aim 1). BMAT analysis has never been done on even this initial smaller scale, so this approach will likely identify factors that directly influence, or are influenced by, MAT. Subsequent, larger-scale automated BMAT analysis, from the remaining Biobank scans, will then allow testing of associations across 100,000 subjects, providing unprecedented power to dissect the causes and consequences of altered MAT.

Determine the impact of BMAT on health and disease - Mendelian Randomisation studies will be done to determine if SNPs associated with altered BMAT (as identified in Aim 2) are also causally associated with physiological and pathological phenomena. This will reveal if alterations in BMAT can directly influence physiological traits and/or the etiology of diverse diseases.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location:

http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you are encouraged to contact the primary supervisor prior to making your application. Additional information on the application process if available from the link above.

For more information about Precision Medicine visit:

http://www.ed.ac.uk/usher/precision-medicine