Bivariate Genome-wide Association Study For Bone Mineral Density And Age At Menarche

Osteoporosis is a common skeletal disease which is a major health problem that affecting a growing number of individuals worldwide. Age at menarche(AAM) is considered as an important factor affecting women health. A later age at menarche is related to longitudinal skeletal growth and mineralization, leading to the fail of reach programmed peak bone mineral density and then with a subsequent higher risk of osteoporosis in old age.The BMD and AAM are traits of high heritability associated to risk of fracture and women health, it is necessary for us to identify if there is any pleiotropic genes/SNPs that contribute to both of the two traits. Previous research has performed a univariate analysis approach on BMD or AAM respectively and it does not explain the potential correlation between them. Here we adopt a novel bivariate genome-wide association study(GWAS) to investigate pleiotropic genes/SNPs that related to both BMD and AAM.Four independent cohorts were included in the study: a discovery sample of826 unrelated Chinese females and three replication samples(1,728 Caucasian females, 712 African-American females and 409 Hispanic-American females. The subjects of the discovery sample and the replication sample were genotyped using Affymetrix Genome-wide Human SNP 6.0 genotyping arrays(Affymetrix, Santa Clara, CA, USA) following the standard protocol recommended by the manufacturer.A final total of 689,368 SNPs were retained for subsequent analyses after quality control(QC). The bivariate GWAS analysis was based on a bivariate linear regression model. We did not find any significant SNPs with p <5×10-8in the discovery sample. However, 4 interesting SNPs were nominally bivariately associated with both AAM and BMD. The four SNPs(rs10817638, rs7851259,rs10982287 and rs4979427), located upstream of the ATP6V1G1 gene, were bivariately associated with hip BMD-AAM(p = 4.90×10-7, 1.07×10-6, 1.28×10-5 and5.42×10-5, respectively). These four SNPs were replicated in African-Americans,with corresponding p values of 1.95×10-2, 3.18×10-2, 2.57 ×10-2and 3.64 ×10-2,respectively. rs10817638 and rs10982287 were further replicated in Caucasians(1.76×10-2and 9.42×10-3, respectively) and Hispanic-Americans(8.37×10-3and1.52×10-3, respectively). Meta-analyses yielded stronger association signals for rs10817638 and rs10982287 with combined p values of 3.02×10-9 and 3.49×10-9,respectively.Previous study shown that ATP6V1G1 was related to both bone resorption and AAM. The ATP6V1G1 identified in this study might be pleiotropy genes for BMD and AAM. The findings in this study would improve our understanding of shared molecular genetic mechanism of BMD and AAM and laid the foundation of related studies in the future to some extent.