REVIEW Osteoporosis: A Silent Disease with Complex Genetic Contribution Maryam Mafi Golchin a , Laleh Heidari b , Seyyed Mohammad Hossein Ghaderian b , Haleh Akhavan-Niaki a, * a Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol 4717647745, Iran b Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences & Health Services, Tehran 1985717443, Iran Received 13 July 2015; revised 30 October 2015; accepted 26 December 2015 Available online 2 January 2016 ABSTRACT Osteoporosis is the most common multifactorial metabolic bone disorder worldwide with a strong genetic component. In this review, the evidence for a genetic contribution to osteoporosis and related phenotypes is summarized alongside with methods used to identify osteoporosis susceptibility genes. The key biological pathways involved in the skeleton and bone development are discussed with a particular focus on master genes clustered in these pathways and their mode of action. Furthermore, the most studied single nucleotide polymorphisms (SNPs) analyzed for their importance as genetic markers of the disease are presented. New data generated by next- generation sequencing in conjunction with extensive meta-analyses should contribute to a better understanding of the genetic basis of osteoporosis and related phenotype variability. These data could be ultimately used for identifying at-risk patients for disease prevention by both controlling environmental factors and providing possible therapeutic targets. KEYWORDS: Osteoporosis; Bone mineral density; Regulatory pathways; Single nucleotide polymorphisms INTRODUCTION Osteoporosis is a common metabolic bone disorder with a strong genetic influence. It is characterized by decrease in bone mass and defects in bone tissue, which weaken bone strength and lead to increased risk of fragility fractures (Kanis et al., 1994; Kamel, 2006). Osteoporosis affects one third of women and one out of eight men over the age of 50 (Li et al., 2010). As bone mass decreases with age during adulthood, osteoporosis is considered as a common disease of the elderly people, also known as a silent disease due to the absence of significant signs before the occurrence of fractures. Conclu- sively, spinal fractures cause pain and most commonly, deformity, loss of height and disability with an increased risk of future fractures (Nevitt et al., 1998), while hip fractures are more painful and often require hospitalization. Susceptibility to osteoporosis results from many different genetic variations and their interaction with environmental factors (Ralston and Uitterlinden, 2010). Correspondingly, up to 60%e80% of Abbreviations: ALDH, aldehyde dehydrogenase; APC, adenomatous pol- yposis coli; APOE, apolipoprotein E; BMD, bone mineral density; CBFA1, core-binding factor A1; CGAS, candidate gene association study; COL1A1, collagen type I a1; CRFs, clinical risk factors; CTNNB1, catenin b1; CYP, cytochrome P450; DBP, vitamin D binding protein; DKK1, Dickkopf1; DMP1, dentin matrix acidic phosphoprotein 1; ER, estrogen receptor; GRP177, G-protein-coupled receptor 177; GWAS, genome-wide association study; HDAC, histone deacetylase; hMSC, human mesenchymal stem cells; IBSP, Integrin-binding sialoprotein; IGF, insulin-like growth factor; IL, interleukin; LRP, low-density lipoprotein receptor-related protein; LS, linkage study; MEF2C, myocyte enhancer factor 2C; OPG, osteoprotegerin; RSPO, R- spondin; PTH, parathyroid hormone; RANKL, receptor activator of NF-kB ligand; RUNX2, runt-related transcription factor 2; SNP, single nucleotide polymorphism; SOST, sclerostin; SOX, sex-determining region Y-box; Sp1, specificity protein 1; TCF/LEF, T cell factor/lymphoid enhancer factor; TGF b, transforming growth factor b; TNFRS11B, tumor necrosis factor receptor superfamily, member 11B; UGT2B17, UDP-glucuronosyl transferase 2B17; VDR, vitamin D receptor. * Corresponding author. Tel/fax: þ98 11 3234 5874. E-mail address: halehakhavan@yahoo.com (H. Akhavan-Niaki). Available online at www.sciencedirect.com ScienceDirect Journal of Genetics and Genomics 43 (2016) 49e61 JGG http://dx.doi.org/10.1016/j.jgg.2015.12.001 1673-8527/Copyright Ó 2015, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Limited and Science Press. All rights reserved.