Genetics of bone mineral density and the associated influence on performance and stress fracture incidence in high-level endurance runners

Low bone mineral density (BMD) is established as a primary predictor of osteoporotic risk but can also have substantial implications for athlete health and injury risk in the elite sporting environment. BMD is a highly multi-factorial phenotype influenced by physical activity and genetics. The exact contribution of these factors and the specific genetic variants association with BMD, particularly in athletic populations, has yet to be determined. Furthermore, few investigations have considered gene-environment interactions - in particular, whether specific genes may be sensitive to mechanical loading from physical activity and the outcome of such an interaction for BMD and potential stress fracture injury risk. Consequently, the overall aim of the current thesis was to investigate the genetic associations with BMD, stress fracture incidence and marathon performance in high-level endurance runners and compare these to a non-athlete cohort to explore genotype-physical activity interactions. BMD differences between endurance runners and non-athletes as well as between runners who had suffered a stress fracture in comparison to those who had not was observed. Additionally, WNT16 rs3801387 and BDNF-AS rs6265 genotype-cohort interactions with BMD were observed whilst P2RX7 rs3751143, COL1A1 rs1800012 and TNFRSF11A rs3018362 genotype associations with BMD were also present. WNT16 rs3801387, COMT rs4680 and P2RX7 rs3751143 were associated with endurance runner status but no variants were associated with performance or stress fracture incidence. These results identify novel genetic associations with BMD and athlete status in an endurance running population as well as genotype-cohort interactions that influence BMD. In conclusion, there appears to be a genotype-dependent influence on athlete status as well as BMD, which may be influenced by physical activity level. Further research is needed to replicate the associations observed in comparable and different populations. Nonetheless, the work presented here has added to our understanding of the genetic associations with performance, BMD and stress fracture incidence, which may have implications for exercise programme management and improving performance in high-level endurance runners