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A large international collaboration has tracked down 15 variations in the genome that are related to the risk of suffering osteoporotic fractures, a major healthcare problem affecting worldwide more than 9 million individuals every year. The collaboration went a step further and used genomic information on other risk factors to examine their causal role on developing fractures; finding that only bone mineral density and muscle strength are directly involved in fracture susceptibility. Genetic predisposition to other clinical risk factors like vitamin D levels and calcium intake, historically considered to be crucial mediators of fracture, were not found to be directly predisposing fracture. These findings postulate that interventions aimed at increasing bone and muscle strength are more likely to be successful in preventing fractures than widespread supplementation of vitamin D or other risk factors not mediating the disease process.
Investigating the Genetic Architecture Underlying the Developmental Origins of Health and Disease
The prevalence of cardiovascular disease, diabetes, osteoporosis and infertility are increasing and the financial burden on society is substantial. Research has shown a link between birth weight and increased risk of these diseases and other cardiovascular/metabolic disorders. Genetics may be involved as not all individuals born of suboptimal weight go on to develop disease. The aims of this research are to: (1) identify novel genes that explain the adverse relationship between birth weight and cardiometabolic disorders, osteoporosis or infertility, (2) determine biological intermediates that partially mediate the relationship between birth weight and these disorders, using genetic profile scores. Currently, most interventions target individuals after the onset of clinical symptoms, by which time treatment is expensive and of limited effectiveness. The Developmental Origins of Health and Disease (DOHaD) paradigm suggests that there may be critical windows earlier in life that offer opportunities for disease treatment and prevention. The overall aim of this project is to use novel statistical genetics methods to identify genes that explain part of the observational association between birth weight and risk of cardiometabolic disease, osteoporosis or infertility, providing a better understanding of this relationship and its implications for future development of disease. We will conduct a genome-wide association study to identify individual genetic variants and regions of the genome that are 1) jointly associated with birth weight and cardiometabolic disorders or osteoporosis, 2) associated with fracture risk or bone related phenotypes and 3) associated with fertility defects. In addition, we will use genetic risk scores for biological characteristics to investigate whether those characteristics partially mediate the observed relationship between birth weight and subsequent risk of disease in later life. Whole cohort with genetic data that have reported their birth weight, diagnosis of cardiometabolic diseases, osteoporosis or fertility defects.