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Approved research

Investigating rare genetic drivers of bone mineral density

Principal Investigator: Mr Matthew Page
Approved Research ID: 37745
Approval date: October 17th 2018

Lay summary

UK Biobank has already significantly contributed to the field of bone biology where the pilot release data was used to explore the contribution of common polymorphisms to bone mineral density; identifying a number of novel BMD loci (Kemp et al, 2017. Nature Genetics). We believe that the allelic spectrum of risk variants for BMD will include novel, rare, low-frequency and common variants. Our proposal can be considered as an extension and complement to the Kemp et al study where we will employ a different analysis strategy to specifically focus on the contribution of rare and very rare variants to BMD with the intention of broadening our understanding of the genetic architecture of a trait with important socio-economic consequence. As a secondary aim, we would like to focus on cohorts of patients where BMD has been assessed in parts of the skeleton that are predominantly cortical bone; a type of bone that is not well addressed by current bone therapeutics. Rare variants are of particular interest because they may be associated with a greater effect on BMD and indeed such a relationship was observed for lower frequency polymorphisms in the Kemp et al study. UCB will adopt an analysis strategy specifically catered to improve power to detect rare variants linked to BMD. By selecting patients with extreme BMD we will focus on the subset of patients where BMD is most likely to be driven by rare variants. Additionally, rather than test association for each variant individually we will assess the burden of rare variants together at different levels of biological organisation; namely the gene and pathway. This proposal includes a clear primary objective which we intend to execute rapidly within 3-5 months and more exploratory secondary objectives that will extend the total run time to approaching a year. This work will be conducted with a multi-disciplinary team of bioinformaticians, statistical geneticists and bone experts from UCB and Immuneering with the intention of validating any novel genetic associations to BMD with the potential to explore the highlighted molecular mechanisms with a view to therapeutic intervention.