Use of Mendelian randomisation to examine the role of abnormal hip shape in the development of hip osteoarthritis

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Context: Osteoarthritis (OA) is a type of joint degeneration that leads to pain and loss of function. Since OA is more common with increasing age, more people are becoming affected as society ages. My research focuses on hip OA, for which joint replacement surgery is the main treatment. In the UK in 2016, there were 80,000 hip replacements for OA costing the NHS £500 million. In a small minority, hip OA results from defective hip development in early life, leading to abnormal hip shape causing aberrant biomechanical forces that accelerate joint destruction. More subtle alterations in hip shape, harder to recognise using standard X-rays, have been suggested to contribute to hip OA development in the wider population. However, since early OA may itself affect hip shape, it's unclear whether hip shape changes reported in association with hip OA are causative factors or simply manifestations of early disease. Mendelian randomisation (MR), a statistical method where genetic factors are used to estimate the causal effect of any given factor independently of confounding, represents an ideal method to address this question. Although MR requires large datasets to ensure sufficient statistical power, the availability of hip DXA scans (a low radiation X-ray) in UK Biobank means that such an approach is now feasible. Aims: I aim to establish whether alterations in hip shape reported to be associated with hip OA, including novel characteristics identified in my preliminary studies, are causal factors in hip OA development, as opposed to a consequence of the disease process. This will be achieved by performing MR analyses in 100,000 individuals from UK Biobank, with hip DXA scans linked to genetic data and information about hip OA. 1) I will extend automatic hip shape measurement to include new hip shape angles and models, using 100,000 DXA scans with UK Biobank2) The same DXA scans will be graded for hip OA, using a further automated process also developed as part of my fellowship 3) I will describe associations between hip shape as characterised in (1), and hip OA as characterised in (2), as well as with other OA-related phenotypes including self-reported hip pain and risk of subsequent hip replacement 4) MR methods will be applied to establish whether associations between hip shape and hip OA described in (3) represent causal relationships Methods: Under the separate Wellcome funded AUGMENT grant which my application will exploit, a method for automating placement of points around the outline of the hip joint (thigh bone and pelvis) will be developed and applied to UK Biobank hip DXA scans. I will use these marked up points in my fellowship, using different subsets and combinations to generate a range of aspects of hip shape, and to classify hip scans for OA according to the presence of osteophytes (bony protuberances) and joint space narrowing. A number of shape parameters thought to be associated with hip OA will be derived, including width relative to height of the upper thigh bone, the angle between the middle of the femoral head (thigh bone) and the edge of the acetabulum (pelvis), and the size of the lesser trochanter (a boney protusion on the inner aspect of the thigh bone).Potential benefits: Identification of alterations in hip shape causing hip OA in the wider population will contribute to our understanding of the causes of OA, particularly the role of altered biomechanical forces. This knowledge will provide the basis for more effective preventative strategies for hip OA, including the role of bespoke exercises, physiotherapy and orthotics, designed to correct the abnormal joint loading predicted to follow from specific shape changes. By studying associations between hip morphology as evaluated by hip DXA and subsequent risk of hip replacement, my fellowship will also contribute to development of use of DXA scans, widely used to screen for osteoporosis, to additionally screen for hip OA.