title: Bivariate Genome-Wide Association Study Implicates ATP6V1G1 as a Novel Pleiotropic Locus Underlying Osteoporosis and Age at Menarche.
abstract: OBJECTIVE
  Age at menarche (AAM) is determined by the overall duration of endocrine-tissue sex hormone exposure levels. Osteoporosis, the most common metabolic bone disease, is characterized primarily by reduced bone mineral density (BMD) and an increased risk of low trauma fractures. Bone was an endocrine organ regulating the synthesis and secretion of sex steroid hormones. The mutual dependence between bone and gonads underscore the importance of genetic approaches to identify novel pleiotropic genetic factors coregulating BMD and AAM. In this study, we performed a bivariate genome-wide association study (GWAS) to explore novel ethnic common loci and/or genes that may influence both AAM and BMD.
  
  
  METHODS
  We analyzed genotyping data available for 826 unrelated Chinese subjects using genome-wide human genotyping arrays. After quality control, a total of 702 413 single-nucleotide polymorphisms (SNPs) were tested for association using a bivariate linear regression model. The interesting SNPs were replicated in three independent cohorts including 1728 unrelated Caucasians, 709 African-Americans, and 408 Hispanic-Americans.
  
  
  RESULTS
  We found 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), P = 1.07 × 10(-6), P = 1.28 × 10(-5), and P = 5.42 × 10(-5), respectively). These four SNPs were replicated in African-Americans, with corresponding values of P = 1.95 × 10(-2), P = 3.18 × 10(-2), P = 2.57 × 10(-2), and P = 3.64 × 10(-2), respectively. rs10817638 and rs10982287 were further replicated in Caucasians (P = 1.76 × 10(-2) and P = 9.42 × 10(-3), respectively) and Hispanic-Americans (P = 8.37 × 10(-3) and P = 1.52 × 10(-3), respectively). Meta-analyses yielded stronger association signals for rs10817638 and rs10982287 with combined values of P = 3.02 × 10(-9) and P = 3.49 × 10(-9), respectively.
  
  
  CONCLUSIONS
  Our study implicated ATP6V1G1 as a novel pleiotropic gene underlying variation of both BMD and AAM. The findings enhance our knowledge of genetic associations between BMD and AAM and provide a rationale for subsequent functional studies of these implicated genes in the pathophysiology of diseases/traits, such as osteoporosis and AAM.
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Li-Jun
authors: LJ
authors: Tan
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Zhuo-Er
authors: ZE
authors: Wang
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Ke-Hao
authors: KH
authors: Wu
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Xiang-Ding
authors: XD
authors: Chen
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Hu
authors: H
authors: Zhu
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Shan
authors: S
authors: Lu
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Qing
authors: Q
authors: Tian
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Xiao-Gang
authors: XG
authors: Liu
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Christopher J
authors: CJ
authors: Papasian
authors: Laboratory of Molecular and Statistical Genetics (L.-J.T., Z.-E.W., K.-H.W., X.-D.C., H.Z., S.L., H.-W.D.), College of Life Sciences, Hunan Normal University, Changsha, Hunan 410081, China; Center of Bioinformatics and Genomics (Q.T., H.-W.D.), School of Public Health and Tropical Medicine, Tulane University, New Orleans, Louisiana 70112; School of Life Science and Technology (X.-G.L.), Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China; and Department of Basic Medical Science (C.J.P.), School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri 64108.
authors: Hong-Wen
authors: HW
authors: Deng
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D041923:Adolescent Development; D000328:Adult; D000368:Aged; D044466:Asian People; D015519:Bone Density; D002681:China; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008572:Menarche / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism; D015663:Osteoporosis, Postmenopausal / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D014481:United States; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; C000594810:ATP6V1G1 protein, human; D025262:Vacuolar Proton-Translocating ATPases