title: Gene-gene interaction between RBMS3 and ZNF516 influences bone mineral density.
abstract: Osteoporosis is characterized by low bone mineral density (BMD), a highly heritable trait that is determined, in part, by the actions and interactions of multiple genes. Although an increasing number of genes have been identified to have independent effects on BMD, few studies have been performed to identify genes that interact with one another to affect BMD. In this study, we performed gene-gene interaction analyses in selected candidate genes in individuals with extremely high versus low hip BMD (20% tails of the distributions), in two independent U.S. Caucasian samples. The first sample contained 916 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 2286 subjects. The second sample consisted of 400 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 1000 subjects. Combining results from these two samples, we found one interacting gene pair (RBMS3 versus ZNF516) which, even after Bonferroni correction for multiple testing, showed consistently significant effects on hip BMD. RMBS3 harbored two single-nucleotide polymorphisms (SNPs), rs6549904 and rs7640046, both of which had significant interactions with an SNP, rs4891159, located on ZNF516 (p = 7.04 × 10(-11) and 1.03 × 10(-10) ). We further validated these results in two additional samples of Caucasian and African descent. The gene pair, RBMS3 versus ZNF516, was successfully replicated in the Caucasian sample (p = 8.07 × 10(-3) and 2.91 × 10(-3) ). For the African sample, a significant interaction was also detected (p = 0.031 and 0.043), but the direction of the effect was opposite to that observed in the three Caucasian samples. By providing evidence for genetic interactions underlying BMD, this study further delineates the genetic architecture of osteoporosis.
authors.affiliation: Key Laboratory of Biomedical Information Engineering of Ministry of Education, and Institute of Molecular Genetics, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, PR China.
authors.forename: Tie-Lin
authors.initials: TL
authors.lastname: Yang
authors.forename: Yan
authors.initials: Y
authors.lastname: Guo
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Hui
authors.initials: H
authors.lastname: Shen
authors.forename: Siyang M
authors.initials: SM
authors.lastname: Li
authors.forename: Siyuan K
authors.initials: SK
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.forename: Yong-Jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Papasian
authors.forename: Hong-Wen
authors.initials: HW
authors.lastname: Deng
mesh_terms: D015519:Bone Density / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D055106:Genome-Wide Association Study; D006615:Hip / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics*; D015203:Reproducibility of Results; D015534:Trans-Activators / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C405932:RBMS3 protein, human; D016601:RNA-Binding Proteins; D015534:Trans-Activators; C000606109:ZNF516 protein, human