Identification Of Pleiotropic Loci For Osteoporosis And Age At Menarche

Epidemiology suggests that osteoporosis is phenotypically and genetically correlated to age at menarche,and they may share the same genetic risk factors,but so far,only a few pleiotropic genes have been reported.In this study,conditional false discovery rate(cFDR)method was used to explore more novel pleiotropic genetic variants with pleiotropic effects on the two related traits,age at menarche(AAM)and lumbar spine(LS)BMD,AAM and forearm(FA)BMD or AAM and femoral neck(FN)BMD.The pleiotropic gene enrichment between osteoporosis and age at menarche was evaluated by stratified condition Q-Q plots,and the results showed that there was pleiotropic enrichment between FA BMD,FN BMD,LS BMD and AAM.When the conditional traits were FA BMD,FN BMD and LS BMD,we identified 1203,1197 and 1195 genetic loci associated with AAM,respectively.When AAM was used as the conditional trait,3 sites were identified to be associated with FA BMD,21 sites were associated with FN BMD,and 24 sites were associated with LS BMD(cFDR<0.05).The conjunction cFDR analysis found that 5 loci were associated with osteoporosis and age at menarche(ccFDR<0.05),CCDC170 rs12197879,ATE1 rs2420970,SMAD3rs7173811,TRPC7 rs889012 and CCDC170 rs11753987.The bayesian fine-mapping PAINTOR method was used to identify the causal variantsin these four pleiotropic genes,Five causal variants(TRPC7 rs183771211,ATE1 rs4752596 and rs2420960,SMAD3 rs76246800 and rs76131938)were identified with a posterior probability greater than 0.9.The identified pleiotropic gene loci and causal variants have deepened our understanding of the mechanism of osteoporosis and age at menarche,and provided certain theoretical basis for subsequent functional experiments and clinical treatment.