title: Bivariate genome-wide association analyses of femoral neck bone geometry and appendicular lean mass.
abstract: 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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan Normal University, Changsha, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Sun
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Tan
authors.forename: Shu-Feng
authors.initials: SF
authors.lastname: Lei
authors.forename: Xiang-Ding
authors.initials: XD
authors.lastname: Chen
authors.forename: Xi
authors.initials: X
authors.lastname: Li
authors.forename: Rong
authors.initials: R
authors.lastname: Pan
authors.forename: Fang
authors.initials: F
authors.lastname: Yin
authors.forename: Quan-Wei
authors.initials: QW
authors.lastname: Liu
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yan
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D044466:Asian People / Q000235:genetics; D001823:Body Composition; D015992:Body Mass Index; D001842:Bone and Bones / Q000033:anatomy & histology*; D005260:Female; D005272:Femur Neck / Q000033:anatomy & histology*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide
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