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Objective  Femoral neck geometric parameters (FNGPs), such as periosteal diameter (W), cross-sectional area (CSA), cortical thickness (CT), buckling ratio (BR), and section modulus (Z), are highly genetically correlated with body lean mass. However, the specific SNPs/genes shared by these phenotypes are largely unknown.    Methods  To identify the specific SNPs/genes shared between FNGPs and appendicular lean mass (ALM), we performed an initial bivariate genome-wide association study (GWAS) by scanning ∼690,000 SNPs in 1,627 unrelated Han Chinese adults (802 males and 825 females) and a follow-up replicate study in 2,286 unrelated US Caucasians.    Results  We identified 13 interesting SNPs that may be important for both FNGPs and ALM. Two SNPs,  rs681900  located in the  HK2  (hexokinase 2) gene and  rs11859916  in the  UMOD  (uromodulin) gene, were bivariately associated with FNGPs and ALM ( p  = 7.58×10 −6  for ALM-BR and  p  = 2.93×10 −6  for ALM-W, respectively). The associations were then replicated in Caucasians, with corresponding  p  values of 0.024 for  rs681900  and 0.047 for  rs11859916 . Meta-analyses yielded combined  p  values of 3.05×10 −6  and 2.31×10 −6  for  rs681900  and  rs11859916 , respectively. Our findings are consistent with previous biological studies that implicated  HK2  and  UMOD  in both FNGPs and ALM. Our study also identified a group of 11 contiguous SNPs, which spanned a region of ∼130 kb, were bivariately associated with FNGPs and ALM, with  p  values ranging from 3.06×10 −7  to 4.60×10 −6  for ALM-BR. The region contained two neighboring miRNA coding genes,  MIR873  (MicroRNA873) and  MIR876  (MicroRNA876).    Conclusion  Our study implicated  HK2, UMOD, MIR873  and  MIR876 , as pleiotropic genes underlying variation of both FNGPs and ALM, thus suggesting their important functional roles in co-regulating both FNGPs and ALM.

Bivariate Genome-Wide Association Analyses of Femoral Neck Bone Geometry and Appendicular Lean Mass