FOXE1 at 9q22 was identified as a BMD candidate gene in the current study. FOXE1 is LY2835219 in vitro involved in thyroid organogenesis and development of cleft palate [18, 19]. A recent study has shown that this gene
is also associated with skeletogenesis in zebrafish. Knocking down of FOXE1 in zebrafish using morpholino resulted in severe reduction in the expression of sox9a, col1a1, and runx2. In addition, this gene and another candidate gene in the same gene family identified in the recent meta-analysis , FOXL1, are downstream targets of Hedgehog-Gli signaling pathway [20, 21]. The Hedgehog and Gli signaling pathway is important in bone development  and osteoblast differentiation . CDK5RAP2 (CDK5 regulatory subunit associated protein 2) at 9q33.2 is involved in the regulation of neuronal differentiation and associated with microcephaly . Microcephaly is a disease in which head size is smaller than average and is often associated GDC-0449 mw with osteoporosis [25, 26]. Adrenergic, alpha-1D-receptor (ADRA1D) at 20p13 is a G-protein coupled receptor that mediates actions in the sympathetic nervous system through a number of neurotransmitters, such as catecholamines, epinephrine, selleck screening library and norepinephrine. The sympathetic nervous system is important in bone mass regulation [27, 28]; male mice without beta1/beta2 adrenergic receptor have
increased cortical bone mass . The role of ADRA1D in bone metabolism has been demonstrated in MC3T3-E1 osteoblast-like
cells, in which ADRA1D is expressed in MC3T3E-1 cells, and RANKL expression is regulated via alpha-adrenergic receptor stimulation in osteoblasts . Eukaryotic translation initiation factor 6 (eIF6) at 20q12 is a gene that controls translation at the rate-limiting step of initiation. Recently, Gandin et al. demonstrated that heterozygous mice of eIF6 had fewer hepatic and adipose cells due to impaired G1/S cell cycle progression . They found that the reduction of adipose tissue was due to a decreased proliferation of pre-adipocytes derived Cediranib (AZD2171) from mesenchymal stem cells. Although bone phenotype was not investigated in their study, we believe that eIF6 could affect bone metabolism by regulating the cell number of osteoblasts, since both adipocytes and osteoblasts are derived from the same progenitor–mesenchymal stem cell; eIF6 also regulates Wnt/beta-catenin signaling via regulation of beta-catenin synthesis . Collectively, our data showed that the BMD genes identified in our meta-analysis play an important role in bone metabolism. Although additional studies will be necessary to validate their function, our current findings indicate that these BMD genes are involved in connective tissue development and function and skeletal and muscular system development and function using bio-function analysis implemented in IPA (p < 0.05) (Tables 6 and 7).