Identification Of Pleiotropic Genes For Both Osteoporosis And Sarcopenia

Osteoporosis and Sarcopenia are two closely related complex diseases commonly observed in the elderly, especially in female. These two conditions do not only share some similar pathophysiology and diagnostic methods but also a lot of risk factors, and they are both the musculoskeletal system diseases. From the evidence of both theoretical and empirical underpinnings, the musculoskeletal system develops, functions, and ages as a whole. Compression strength index (CSI) of femoral neck (FN) is a newly developed phenotype for osteoporosis, and it is based on theoretical considerations from a biomechanical viewpoint to improve the performance of risk assessment of hip fractures. Appendicular lean mass (ALM) a currently acceptable measure in diagnosing sarcopenia. Previous studies have indicated that CSI and ALM might be correlated, but the the co-regulation mechanism and the shared SNPs/genes between them are largely unknown.Nowadays, GWAS is normally performed in a univariate framework, which analyzes different phenotypes separately. Therefore the univariate analysis may ignore the genetic correlation to many human diseases. Bivariate GWAS is a good method to solve the problem, which is more powerful to detect pleiotropic genes than the univariate approach. This study performed an initial bivariate genome-wide association study (GWAS) to identify the specific SNPs/genes shared by CSI and ALM in1728unrelated US Caucasian women and a follow-up replicate study in825unrelated female Chinese adults. Bone mineral density (BMD), bone size at FN and ALM were measured by dual-energy X-ray absorptiometry (DXA),then CSI is calculated as follows:CSI=(BMD×FNW)/Weight. Using the Affymetrix GeneChip Human Mapping SNP6.0arrays,about900,000eligible SNPs were genotyped and746,709SNPs were selected for the subsequent association analyses with the R software.Three SNPs may be associated with both CSI and ALM. The association signals for two SNPs (p=1.88×10-8for rs11665492in NDUFV2gene and p=5.78×10-8for rs10225647in FAM3C) are significant according to GWAS significant level. The third SNPs (p=8.79×10-7for rs12878930in ESRRB) have strong association signals in the initial GWAS. More importantly, the SNP was also significantly associated with both CSI and ALM (p=0.003) in Chinese female, which is an obviously different in genetic background. Earlier researches have indicated that NDUFV2might have indirect influence on both CSI and ALM. However, the function of FAM3C and ESRRB were largely unknown. Our study accounted that the pleiotropism of NDUFV2, FAM3C and ESRRB induced the variation of both CSI and ALM, providing a rationale for subsequent functional studies of these implicated genes in the pathophysiology of diseases related to them, such as osteoporosis and sarcopenia.