Using Genetics to Identify Causal Pathways that Influence Bone Related Phenotypes in Children and Young Adults.

Our aim is to identify genes and biological pathways that influence the density of bones in children and young adults, and consequently future risk of osteoporosis (a disease characterized by thin and brittle bones). This is important because approximately half of British women and one in five men will suffer from osteoporosis at some stage in their lives, costing the NHS in excess of £1.8 billion. Currently most of our knowledge concerning the genes influencing osteoporosis has come from studies of older individuals. These genes are thought to regulate bone loss. However there is a growing realization that it is also important to study bone growth in children and young adults. This is because the genes that contribute to bone growth may be different from the ones that affect bone loss, and how dense an individual’s bones are in young adulthood is a strong predictor of whether they will develop osteoporosis in later life. We will identify genes which affect bone density by correlating measures of bone with millions of genetic markers in thousands of children and young adults. The identification of genes and biological pathways that influence osteoporosis represents the first step in developing new therapies to help treat the condition.

This Programme will focus on identifying genetic variants and biological pathways that causally influence bone related phenotypes in children and young adults. Bone mineral density (BMD) as measured by Dual X-ray Absorptiometry (DXA) is the primary diagnostic and prognostic marker for osteoporosis and fracture susceptibility in adults as it quantifies the relative strength and fracture risk of the measured bone. Growing evidence from our lab and our collaborators suggest that there is considerable value in examining BMD in children and young adults. This is important, not only because peak bone mass is one of the strongest known predictors of future osteoporosis, but also because the genetic variants that influence bone acquisition may differ in strength and identity from those that influence bone maintenance and bone loss in later life. Given that osteoporosis will at some stage affect approximately half of British women and one in five men, it is important to study BMD throughout the life course so that one can completely understand the factors influencing bone and consequently future risk of osteoporosis.
Genetic variation affecting bone-related phenotypes will be identified using a combination of cutting edge genetic technologies including next generation sequencing and high resolution bone-related phenotypes that have been measured longitudinally in the Avon Longitudinal Study of Parents and Children (ALSPAC). Data will be analysed using a combination of advanced and established statistical methodologies which will then be meta-analyzed and replicated in collaboration with cohort studies with similar data. Genetic loci that influence gene methylation, expression, and metabolites will be identified through the genetic association analysis of genome-wide SNP and sequencing data within ALSPAC. Using a combination of new and existing statistical methodology, allelic scores that index levels of these molecular phenotypes will be constructed, validated and subsequently tested for association with bone mineral density (BMD) and osteoporosis, identifying potentially modifiable intermediate biological pathways affecting these phenotypes. Formal Mendelian randomization analysis and extensions of this approach will be performed to confirm that these associations are likely to represent causal relationships. The Programme will use pre-existing data that has been funded from a large number of sources and many grants that will still be active when the Unit starts. The Programme will require the support of postdoctoral research staff for its aims to be realised, and the analysis pipelines and protocols generated within it will serve as a platform for the genetic analysis of the thousands of other phenotypes within the ALSPAC cohort, benefiting the many investigators, both internal and external to the Unit, who use the ALSPAC resource for their own genetic investigations.