Bivariate Genome-wide Association Analyses Of Femoral Neck Bone Geometry And Percent Fat Mass

Obesity and osteoporosis are two complex diseases and become a major public health challenge worldwide. Osteoporosis is a common public disease characterized by decreasing of bone strength and increasing of fracture risk with advanced age. Obesity is a disease of excess body fat, which increases the risk of several common diseases.Bone geometry and percent fat mass (PFM) are important index for bone and obesity. Femoral neck geometric parameters (FNGPs), such as periosteal diameter (W), cortical thickness (CT), cross-sectional area (CSA), section modulus (Z), and buckling ratio (BR), are closely genetically correlated with percent fat mass (PFM). However, the shared SNP/gene between them are largely unknown. Bivariate analyses have been proven to be an effective method to detect pleiotropic genes.To identify the specific SNP/gene shared between FNGPs and percent fat mass (PFM), bivariate genome-wide association study (GWAS) was carried out in a large Chinese population.A total of1,627unrelated Han Chinese adults (802males and825females) were recruited for this bivariate GWAS. The five FNGPs are calculated based on the BMD and bone size at the femoral neck (FN). Bone mineral density (BMD) and bone size at the FN and PFM were measured by dual-energy X-ray absorptiometry (DXA). About900,000eligible SNPs were genotyped by using Affymetrix GeneChip Human Mapping SNP6.0arrays, and689,368SNPs were selected for the subsequent association analyses. Based on a linear model, bivariate regression analyses were performed to detect association between a SNP and two phenotypes. The SNPs that ranked at the top of all the about690,000SNPs were then replicated in2,286unrelated US Caucasians.We identified10interesting SNPs that may be important for both FNGPs and PFM. SNP rs7995696of the LINC00540(long intergenic non-protein coding RNA540) gene, was bivariately associated with FNGPs and PFM (p=7.58×10-6for PFM-Z). The associations were then replicated in Caucasians, with corresponding p values of0.023. Meta-analyses yielded combined p values of2.87×10"6for rs7995696. Moreover, another two SNPs, rs4127398and rs4908185were suggested strong association signals across the five phenotype pairs, with p values ranging from9.88×10-7to6.26×10-6and5.03×10-6to9.85×10-6, respectively. SNP rs4127398located at～50kb downstream of the PIWIL4(piwi-like4) gene and at-100kb upstream of the AMOTL1(angiomotin like1) gene, meanwhile, SNP rs4908185located within OLFM3(olfactomedin3) gene.Our study also identified a group of7contiguous SNPs spanning～60kb region harboring the MAGEA1(melanoma antigen family A,1) gene, were bivariately associated with FNGPs and PFM, with p values ranging from4.13×10-6to9.98×10-6for PFM-W.Our study implicated LINC00540,PIWIL4,MOTL1,OLFM3, and MAGEA1, as pleiotropic genes underlying variation of both FNGPs and PFM, thus suggesting their important functional roles in co-regulating both FNGPs and PFM.