Identification Of Pleotropic Genes Influencing Both Bone Geometry Parameters And Appendicular Lean Mass In Caucasian Woman

Osteoporosis is a public health problem characterized by low bone mass, poor bone quality, and increased fracture risk. Bone geometry, an essential clinical predictor of fracture, is play an important role in determining bone strength, independent of bone mineral density (BMD). Large cohort studies have shown femoral neck geometric parameter (FNGP) are associated with osteoporotic fractures directly, including periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), buckling ratio(BR), and section modulus (Z).Sarcopenia is a syndrome characterized by progressive and generalized loss of skeletal muscle mass and strength. Body lean mass is the distinguished standard for assessment of sarcopenia. As many studies have suggested that appendicular lean mass (ALM) is a good representative method of body skeletal muscle mass for assessing exercise capacity and predicting related diseases than total body lean mass. We adopted ALM as the determinant of lean mass, which is calculated as the total of lean mass in the arms and legs.Osteoporosis and sarcopenia were the age-related diseases, with high heritability. Studies have found that, with advanced age, these two diseases often occur simultaneously. Thus FNGPs and ALM are biologically correlated traits and are important determinants for bone strength and fracture risk. Previous studies have indicated that FNGPs and ALM are highly genetically associated, which highlighted that they may share some common genetic factors, however, the specific genes/SNPs shared by FNGPs and ALM are largely unclear.Bivariate genome-wide association study (GWAS) is an effective approach to identify genes/SNPs influencing two correlated traits. By incorporating correlation information, bivariate GWAS analysis can improve the statistical power considerably and facilitate the identification of gene/SNPs whose effects are too small to be detected by univariate analyses. To identify the specific genes/SNPs influencing both FNGPs and ALM, we performed an initial bivariate GWAS in1728Caucasian females and replicated important findings in802unrelated Han Chinese females.We identified five SNPs, rs4978766, rs12351693, rs2274926, rs4978378and rs4978765which located in CTNNAL1(cadherin-associated protein, alpha-like1) gene, was bivariately associated with FNGPs and ALM with p values ranging from2.15×10-6to9.91×10-6. The five SNPs were replicated in Chinese females with p values ranging from0.013to0.047. Combined p values of meta-analyses varied from1.45×10-6to5.20×10-6. However, these SNPs did not show association signals in the Caucasian males, with corresponding initial p values ranging from0.053to0.253. We also identified six SNPs, rs2015621, rs4959869, rs4959861, rs9378813, rs13194192and rs9378381, which located in/around C6orfl45(chromosome6open reading frame145) gene. For example, the SNP rs2015621was bivariately associated with FNGPs and ALM (p=1.63×10-8, Bonferroni adjusted p=0.015for ALM-CSA; p=4.73×10-8, Bonferroni adjusted p=0.043for ALM-CT; p=3.49×10-7in original GWAS and p=0.031in replication study for ALM-Z with combined p value of meta-analyses2.12×10-7). But the SNP did not associated with FNGPs and ALM in the Caucasian males, with corresponding initial p values of0.800for ALM-CSA;0.993for ALM-CT and0.474for ALM-Z.In conclusion, our study suggested CTNNAL1and C6orfl45are pleotropic sex-specific genes underlying co-variation of FNGPs and ALM. Previous biological studies on the CTNNAL1gene support the dual roles in both bone geometry and ALM. The functions of C6orfl45genes related to bone metabolism and muscle are largely unknown and further studies are needed to delineate the function of the gene in the co-regulation both FNGPs and ALM.