Genetic risk for the polycystic ovary syndrome, bone mineral density and fractures in women and men: A UK Biobank Mendelian randomisation study

Introduction: There is conflicting data on the effect of polycystic ovary syndrome (PCOS) on bone mineral density (BMD) and fracture risk. Recent genetic data suggest that men may also carry genetic risk factors for PCOS; the associations of these factors with parameters of bone health remains unknown. We aimed to investigate if the genetic risk of PCOS is associated with BMD and fracture risk in women and men in the UK Biobank dataset. Methods: We used Mendelian randomisation (MR) analysis to test the association of genetic risk of excess testosterone in PCOS with BMD and fractures in the UK biobank study. The MR analysis was performed using linear regression analysis with the weighted genetic risk score (wGRS) as an independent variable adjusting for age, BMI and population eigenvectors. The horizontal pleiotmpy in the MR analysis was tested using MR-Egger regression analysis. Results: The study consisted of 221,086 Caucasian women (mean age +/- SD: 56.7 +/- 7.9 years, mean body mass index [BMI] +/- SD: 27.0 +/- 5.1 kg/m(2), mean BMD SD: 0.50 +/- 0.11 g/cm(2)) and 187,816 Caucasian men (mean age +/- SD: 57.1 +/- 8.1 years, mean BMI + SD: 27.7 +/- 4.1 kg/m 2 and mean BMD SD: 0.56 +/- 0.12 g/cm(2)). Women and men self-reported 24,797 (11%) and 17,076 (10%) fractures over the last 5 years, respectively. The MR analysis showed that one SD increase in the wGRS for clinical or biochemical hyperandrogenism in PCOS was associated with significantly higher heel BMD (Beta = 0.0007 [+0.0002], P-value = 0.001) and a significantly reduced risk of fractures (OR = 0.97, P-value = 0.003) in women. A similar wGRS in men was not associated with BMD or risk of fractures. Conclusion: In this study, we showed that the excess genetic risk for hyperandrogenism in women with PCOS is associated with a higher BMD and reduced risk of fractures.