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

Abstract

ObjectiveFemoral 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.MethodsTo 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.ResultsWe 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).ConclusionOur 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.

Genetic aspects of skeletal muscle strength and mass with relevance to sarcopenia

“…Importantly, these associations were confirmed in three replication cohorts consisting of over 6000 total white and Chinese subjects. Sun et al 57 recently identified several novel candidate polymorphisms underlying both appendicular lean mass and femoral neck geometric properties in a large GWAS in Chinese adults followed by independent replication in white subjects. Most recently, Hai and colleagues 58 performed a copy-number variation GWAS in this same Chinese cohort and identified the Gremlin1 gene as significantly associated with lean mass.…”

Genomics and metabolomics of muscular mass in a community-based sample of UK females

“…Because of this important advantage, APLM is currently widely used in assessment of a sarcopenic status of an individual 14 as well as in variety of the genetic studies, for example. 15,16 We used a large sample of middle-aged UK female twins, who were assessed using whole body DXA, metabolomic (MTB) screening and genome-wide association scans imputed to 2.5 million variants. In addition, since we were interested in accurate estimation of common and variable-specific genetic and environmental effects on LBM and its associated metabolites, we also implemented a newly developed modification of bivariate analysis, reported here for the first time.…”

The Impact of Large-Scale Genomic Methods in Orthopaedic Disorders: Insights from Genome-Wide Association Studies

“…Few of these report significant genetic associations with skeletal traits (Table II). Of the orthopaedic-related studies, the majority assessed quantitative traits such as measures of bone morphology [38][39][40][41] or bone integrity 42,43 rather than associations with the presence or absence of disease. Genetic studies directed at osteoporosis phenotypes outnumber other GWASs of diseases with orthopaedic involvement, and these have been extensively reviewed elsewhere 44 .…”