Unveiling the mysteries of the genetics of osteoporosis

Journal of Endocrinological Investigation

Volumn 37, Issue 10, 2014, Pages 925-934

  Alonso, N ^a   Ralston, S H ^a  

^a UNIVERSITY OF EDINBURGH   (United Kingdom)

Author keywords

GWAS; Linkage analysis; NF B signalling; Osteoporosis; Whole genome sequencing; Wnt signalling

Indexed keywords

RECEPTOR ACTIVATOR OF NUCLEAR FACTOR KAPPA B; WNT PROTEIN; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN;

BONE CELL; BONE DENSITY; BONE MASS; BONE METABOLISM; CELL ACTIVITY; COHORT ANALYSIS; ENVIRONMENTAL FACTOR; EXOME; GENE IDENTIFICATION; GENE LOCUS; GENE SEQUENCE; GENETIC ASSOCIATION; GENETIC VARIABILITY; HUMAN; HUMAN GENETICS; LINKAGE ANALYSIS; NONHUMAN; OSTEOPOROSIS; REVIEW; WNT SIGNALING PATHWAY; GENETICS; PHYSIOLOGY; SIGNAL TRANSDUCTION;

GENOME-WIDE ASSOCIATION STUDY; HUMANS; NF-KAPPA B; OSTEOPOROSIS; SIGNAL TRANSDUCTION; WNT PROTEINS;

EID: 84940932403     PISSN: 03914097     EISSN: 17208386     Source Type: Journal    
DOI: 10.1007/s40618-014-0149-7     Document Type: Review

References (77)

1. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A (2007) Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res 22:465-475. doi: 10.1359/jbmr.061113
2. Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254-1259
3. Jergas M, Gluer CC (1997) Assessment of fracture risk by bone density measurements. Semin Nucl Med 27:261-275
4. Ferrari S (2008) Human genetics of osteoporosis. Best Pract Res Clin Endocrinol Metab 22:723-735. doi: 10.1016/j.beem.2008.08.007
5. Chen Y, Shen H, Yang F, Liu PY, Tang N, Recker RR, Deng HW (2009) Choice of study phenotype in osteoporosis genetic research. J Bone Miner Metab 27:121-126. doi: 10.1007/s00774-008-0020-z
6. Cummings SR, Nevitt MC, Browner WS, Stone K, Fox KM, Ensrud KE, Cauley J, Black D, Vogt TM (1995) Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group. N Engl J Med 332:767-773. doi: 10.1056/NEJM199503233321202
7. Torgerson DJ, Campbell MK, Thomas RE, Reid DM (1996) Prediction of perimenopausal fractures by bone mineral density and other risk factors. J Bone Miner Res 11:293-297. doi: 10.1002/jbmr.5650110219
8. Deng HW, Chen WM, Recker S, Stegman MR, Li JL, Davies KM, Zhou Y, Deng H, Heaney R, Recker RR (2000) Genetic determination of Colles' fracture and differential bone mass in women with and without Colles' fracture. J Bone Miner Res 15:1243-1252. doi: 10.1359/jbmr.2000.15.7.1243
9. Andrew T, Antioniadis L, Scurrah KJ, MacGregor AJ, Spector TD (2005) Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD. J Bone Miner Res 20:67-74
10. Almasy L, Blangero J (1998) Multipoint quantitative-trait linkage analysis in general pedigrees. Am J Hum Genet 62:1198-1211
11. Abecasis GR, Cherny SS, Cookson WO, Cardon LR (2002) Merlin-rapid analysis of dense genetic maps using sparse gene flow trees. Nat Genet 30:97-101
12. Nyholt DR (2000) All LODs are not created equal. Am J Hum Genet 67:282-288
13. Sawcer SJ, Maranian M, Singlehurst S, Yeo T, Compston A, Daly MJ, De Jager PL, Gabriel S, Hafler DA, Ivinson AJ, Lander ES, Rioux JD, Walsh E, Gregory SG, Schmidt S, Pericak-Vance MA, Barcellos L, Hauser SL, Oksenberg JR, Kenealy SJ, Haines JL (2004) Enhancing linkage analysis of complex disorders: an evaluation of high-density genotyping. Hum Mol Genet 13:1943-1949. doi: 10.1093/hmg/ddh202
14. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams TC, Lubahn DB, Korach KS (1994) Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med 331:1056-1061. doi: 10.1056/NEJM199410203311604
15. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K (1995) Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab 80:3689-3698. doi: 10.1210/jcem.80.12.8530621
16. Janssens K, Gershoni-Baruch R, Guanabens N, Migone N, Ralston S, Bonduelle M, Lissens W, Van ML, Vanhoenacker F, Verbruggen L, Van HW (2000) Mutations in the gene encoding the latency-associated peptide of TGF-beta 1 cause Camurati-Engelmann disease. Nat Genet 26:273-275. doi: 10.1038/81563
17. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De PA, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van HW, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML (2001) LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell 107:513-523
18. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP (2002) High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med 346:1513-1521. doi: 10.1056/NEJMoa013444
19. Balemans W, Ebeling M, Patel N, Van HE, Olson P, Dioszegi M, Lacza C, Wuyts W, Van Den Ende J, Willems P, Paes-Alves AF, Hill S, Bueno M, Ramos FJ, Tacconi P, Dikkers FG, Stratakis C, Lindpaintner K, Vickery B, Foernzler D, Van HW (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10:537-543
20. Balemans W, Patel N, Ebeling M, Van HE, Wuyts W, Lacza C, Dioszegi M, Dikkers FG, Hildering P, Willems PJ, Verheij JB, Lindpaintner K, Vickery B, Foernzler D, Van HW (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39:91-97
21. Balemans W, Van WL, Van HW (2005) A clinical and molecular overview of the human osteopetroses. Calcif Tissue Int 77:263-274. doi: 10.1007/s00223-005-0027-6
22. Sobacchi C, Frattini A, Guerrini MM, Abinun M, Pangrazio A, Susani L, Bredius R, Mancini G, Cant A, Bishop N, Grabowski P, Del FA, Messina C, Errigo G, Coxon FP, Scott DI, Teti A, Rogers MJ, Vezzoni P, Villa A, Helfrich MH (2007) Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nat Genet 39:960-962. doi: 10.1038/ng2076
23. Guerrini MM, Sobacchi C, Cassani B, Abinun M, Kilic SS, Pangrazio A, Moratto D, Mazzolari E, Clayton-Smith J, Orchard P, Coxon FP, Helfrich MH, Crockett JC, Mellis D, Vellodi A, Tezcan I, Notarangelo LD, Rogers MJ, Vezzoni P, Villa A, Frattini A (2008) Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. Am J Hum Genet 83:64-76. doi: 10.1016/j.ajhg.2008.06.015
24. Barnes AM, Chang W, Morello R, Cabral WA, Weis M, Eyre DR, Leikin S, Makareeva E, Kuznetsova N, Uveges TE, Ashok A, Flor AW, Mulvihill JJ, Wilson PL, Sundaram UT, Lee B, Marini JC (2006) Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta. N Engl J Med 355:2757-2764. doi: 10.1056/NEJMoa063804
25. Cabral WA, Chang W, Barnes AM, Weis M, Scott MA, Leikin S, Makareeva E, Kuznetsova NV, Rosenbaum KN, Tifft CJ, Bulas DI, Kozma C, Smith PA, Eyre DR, Marini JC (2007) Prolyl 3-hydroxylase 1 deficiency causes a recessive metabolic bone disorder resembling lethal/severe osteogenesis imperfecta. Nat Genet 39:359-365. doi: 10.1038/ng1968
26. Marini JC, Forlino A, Cabral WA, Barnes AM, San Antonio JD, Milgrom S, Hyland JC, Korkko J, Prockop DJ, De PA, Coucke P, Symoens S, Glorieux FH, Roughley PJ, Lund AM, Kuurila-Svahn K, Hartikka H, Cohn DH, Krakow D, Mottes M, Schwarze U, Chen D, Yang K, Kuslich C, Troendle J, Dalgleish R, Byers PH (2007) Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans. Hum Mutat 28:209-221. doi: 10.1002/humu.20429
27. Barnes AM, Carter EM, Cabral WA, Weis M, Chang W, Makareeva E, Leikin S, Rotimi CN, Eyre DR, Raggio CL, Marini JC (2010) Lack of cyclophilin B in osteogenesis imperfecta with normal collagen folding. N Engl J Med 362:521-528. doi: 10.1056/NEJMoa0907705
28. van Dijk FS, Zillikens MC, Micha D, Riessland M, Marcelis CL, de Die-Smulders CE, Milbradt J, Franken AA, Harsevoort AJ, Lichtenbelt KD, Pruijs HE, Rubio-Gozalbo ME, Zwertbroek R, Moutaouakil Y, Egthuijsen J, Hammerschmidt M, Bijman R, Semeins CM, Bakker AD, Everts V, Klein-Nulend J, Campos-Obando N, Hofman A, te Meerman GJ, Verkerk AJ, Uitterlinden AG, Maugeri A, Sistermans EA, Waisfisz Q, Meijers-Heijboer H, Wirth B, Simon ME, Pals G (2013) PLS3 mutations in X-linked osteoporosis with fractures. N Engl J Med 369:1529-1536. doi: 10.1056/NEJMoa1308223
29. Risch NJ (2000) Searching for genetic determinants in the new millennium. Nature 405:847-856. doi: 10.1038/35015718
30. Kaufman JM, Ostertag A, Saint-Pierre A, Cohen-Solal M, Boland A, Van PI, Toye K, de Vernejoul MC, Martinez M (2008) Genome-wide linkage screen of bone mineral density (BMD) in European pedigrees ascertained through a male relative with low BMD values: evidence for quantitative trait loci on 17q21-23, 11q12-13, 13q12-14, and 22q11. J Clin Endocrinol Metab 93:3755-3762. doi: 10.1210/jc.2008-0678
31. Peacock M, Koller DL, Lai D, Hui S, Foroud T, Econs MJ (2009) Bone mineral density variation in men is influenced by sex-specific and non sex-specific quantitative trait loci. Bone 45:443-448. doi: 10.1016/j.bone.2009.05.002
32. Xiao P, Shen H, Guo YF, Xiong DH, Liu YZ, Liu YJ, Zhao LJ, Long JR, Guo Y, Recker RR, Deng HW (2006) Genomic regions identified for BMD in a large sample including epistatic interactions and gender-specific effects. J Bone Miner Res 21:1536-1544. doi: 10.1359/jbmr.060717
33. Wise LH, Lanchbury JS, Lewis CM (1999) Meta-analysis of genome searches. Ann Hum Genet 63:263-272
34. Lee YH, Rho YH, Choi SJ, Ji JD, Song GG (2006) Meta-analysis of genome-wide linkage studies for bone mineral density. J Hum Genet 51:480-486. doi: 10.1007/s10038-006-0390-9
35. Ioannidis JP, Ng MY, Sham PC, Zintzaras E, Lewis CM, Deng HW, Econs MJ, Karasik D, Devoto M, Kammerer CM, Spector T, Andrew T, Cupples LA, Duncan EL, Foroud T, Kiel DP, Koller D, Langdahl B, Mitchell BD, Peacock M, Recker R, Shen H, Sol-Church K, Spotila LD, Uitterlinden AG, Wilson SG, Kung AW, Ralston SH (2007) Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass. J Bone Miner Res 22:173-183. doi: 10.1359/jbmr.060806
36. Styrkarsdottir U, Cazier JB, Kong A, Rolfsson O, Larsen H, Bjarnadottir E, Johannsdottir VD, Sigurdardottir MS, Bagger Y, Christiansen C, Reynisdottir I, Grant SF, Jonasson K, Frigge ML, Gulcher JR, Sigurdsson G, Stefansson K (2003) Linkage of osteoporosis to chromosome 20p12 and association to BMP2. PLoS Biol 1:E69. doi: 10.1371/journal.pbio.0000069
37. Tranah GJ, Taylor BC, Lui LY, Zmuda JM, Cauley JA, Ensrud KE, Hillier TA, Hochberg MC, Li J, Rhees BK, Erlich HA, Sternlicht MD, Peltz G, Cummings SR (2008) Genetic variation in candidate osteoporosis genes, bone mineral density, and fracture risk: the study of osteoporotic fractures. Calcif Tissue Int 83:155-166. doi: 10.1007/s00223-008-9165-y
38. Medici M, van Meurs JB, Rivadeneira F, Zhao H, Arp PP, Hofman A, Pols HA, Uitterlinden AG (2006) BMP-2 gene polymorphisms and osteoporosis: the Rotterdam Study. J Bone Miner Res 21:845-854. doi: 10.1359/jbmr.060306
39. Richards JB, Kavvoura FK, Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Zillikens MC, Wilson SG, Mullin BH, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra BA, Pols HA, Sigurdsson G, Thorsteinsdottir U, Soranzo N, Williams FM, Zhou Y, Ralston SH, Thorleifsson G, van Duijn CM, Kiel DP, Stefansson K, Uitterlinden AG, Ioannidis JP, Spector TD (2009) Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med 151:528-537
40. Ioannidis JP (2005) Why most published research findings are false. PLoS Med 2:e124. doi: 10.1371/journal.pmed.0020124
41. Kryukov GV, Shpunt A, Stamatoyannopoulos JA, Sunyaev SR (2009) Power of deep, all-exon resequencing for discovery of human trait genes. Proc Natl Acad Sci USA 106:3871-3876. doi: 10.1073/pnas.0812824106
42. Sims AM, Shephard N, Carter K, Doan T, Dowling A, Duncan EL, Eisman J, Jones G, Nicholson G, Prince R, Seeman E, Thomas G, Wass JA, Brown MA (2008) Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes. J Bone Miner Res 23:499-506. doi: 10.1359/jbmr.071113
43. Ioannidis JP, Ralston SH, Bennett ST, Brandi ML, Grinberg D, Karassa FB, Langdahl B, van Meurs JB, Mosekilde L, Scollen S, Albagha OM, Bustamante M, Carey AH, Dunning AM, Enjuanes A, van Leeuwen JP, Mavilia C, Masi L, McGuigan FE, Nogues X, Pols HA, Reid DM, Schuit SC, Sherlock RE, Uitterlinden AG (2004) Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes. JAMA 292:2105-2114. doi: 10.1001/jama.292.17.2105
44. Ralston SH, Uitterlinden AG, Brandi ML, Balcells S, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Scollen S, Bustamante M, Husted LB, Carey AH, Diez-Perez A, Dunning AM, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, del MF, Pols HA, Reeve J, Reid DM, Renner W, Rivadeneira F, van Schoor NM, Sherlock RE, Ioannidis JP (2006) Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study. PLoS Med 3:e90 doi: 10.1371/journal.pmed.0030090
45. Langdahl BL, Uitterlinden AG, Ralston SH, Trikalinos TA, Balcells S, Brandi ML, Scollen S, Lips P, Lorenc R, Obermayer-Pietsch B, Reid DM, Armas JB, Arp PP, Bassiti A, Bustamante M, Husted LB, Carey AH, Perez CR, Dobnig H, Dunning AM, Fahrleitner-Pammer A, Falchetti A, Karczmarewicz E, Kruk M, van Leeuwen JP, Masi L, van Meurs JB, Mangion J, McGuigan FE, Mellibovsky L, Mosekilde L, Nogues X, Pols HA, Reeve J, Renner W, Rivadeneira F, van Schoor NM, Ioannidis JP (2008) Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study. Bone 42:969-981. doi: 10.1016/j.bone.2007.11.007
46. Uitterlinden AG, Ralston SH, Brandi ML, Carey AH, Grinberg D, Langdahl BL, Lips P, Lorenc R, Obermayer-Pietsch B, Reeve J, Reid DM, Amedei A, Bassiti A, Bustamante M, Husted LB, Diez-Perez A, Dobnig H, Dunning AM, Enjuanes A, Fahrleitner-Pammer A, Fang Y, Karczmarewicz E, Kruk M, van Leeuwen JP, Mavilia C, van Meurs JB, Mangion J, McGuigan FE, Pols HA, Renner W, Rivadeneira F, van Schoor NM, Scollen S, Sherlock RE, Ioannidis JP (2006) The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis. Ann Intern Med 145:255-264
47. Kiel DP, Demissie S, Dupuis J, Lunetta KL, Murabito JM, Karasik D (2007) Genome-wide association with bone mass and geometry in the Framingham Heart Study. BMC Med Genet 8(Suppl 1):S14. doi: 10.1186/1471-2350-8-S1-S14
48. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Center JR, Nguyen TV, Bagger Y, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K (2008) Multiple genetic loci for bone mineral density and fractures. N Engl J Med 358:2355-2365. doi: 10.1056/NEJMoa0801197
49. Richards JB, Rivadeneira F, Inouye M, Pastinen TM, Soranzo N, Wilson SG, Andrew T, Falchi M, Gwilliam R, Ahmadi KR, Valdes AM, Arp P, Whittaker P, Verlaan DJ, Jhamai M, Kumanduri V, Moorhouse M, van Meurs JB, Hofman A, Pols HA, Hart D, Zhai G, Kato BS, Mullin BH, Zhang F, Deloukas P, Uitterlinden AG, Spector TD (2008) Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet 371:1505-1512. doi: 10.1016/S0140-6736(08)60599-1
50. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, Gudbjartsson DF, Walters GB, Ingvarsson T, Jonsdottir T, Saemundsdottir J, Snorradottir S, Center JR, Nguyen TV, Alexandersen P, Gulcher JR, Eisman JA, Christiansen C, Sigurdsson G, Kong A, Thorsteinsdottir U, Stefansson K (2009) New sequence variants associated with bone mineral density. Nat Genet 41:15-17. doi: 10.1038/ng.284
51. Xiong DH, Liu XG, Guo YF, Tan LJ, Wang L, Sha BY, Tang ZH, Pan F, Yang TL, Chen XD, Lei SF, Yerges LM, Zhu XZ, Wheeler VW, Patrick AL, Bunker CH, Guo Y, Yan H, Pei YF, Zhang YP, Levy S, Papasian CJ, Xiao P, Lundberg YW, Recker RR, Liu YZ, Liu YJ, Zmuda JM, Deng HW (2009) Genome-wide association and follow-up replication studies identified ADAMTS18 and TGFBR3 as bone mass candidate genes in different ethnic groups. Am J Hum Genet 84:388-398. doi: 10.1016/j.ajhg.2009.01.025
52. Rivadeneira F, Styrkarsdottir U, Estrada K, Halldorsson BV, Hsu YH, Richards JB, Zillikens MC, Kavvoura FK, Amin N, Aulchenko YS, Cupples LA, Deloukas P, Demissie S, Grundberg E, Hofman A, Kong A, Karasik D, van Meurs JB, Oostra B, Pastinen T, Pols HA, Sigurdsson G, Soranzo N, Thorleifsson G, Thorsteinsdottir U, Williams FM, Wilson SG, Zhou Y, Ralston SH, van Duijn CM, Spector T, Kiel DP, Stefansson K, Ioannidis JP, Uitterlinden AG (2009) Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nat Genet 41:1199-1206. doi: 10.1038/ng.446
53. Kung AW, Xiao SM, Cherny S, Li GH, Gao Y, Tso G, Lau KS, Luk KD, Liu JM, Cui B, Zhang MJ, Zhang ZL, He JW, Yue H, Xia WB, Luo LM, He SL, Kiel DP, Karasik D, Hsu YH, Cupples LA, Demissie S, Styrkarsdottir U, Halldorsson BV, Sigurdsson G, Thorsteinsdottir U, Stefansson K, Richards JB, Zhai G, Soranzo N, Valdes A, Spector TD, Sham PC (2010) Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies. Am J Hum Genet 86:229-239. doi: 10.1016/j.ajhg.2009.12.014
54. Hsu YH, Zillikens MC, Wilson SG, Farber CR, Demissie S, Soranzo N, Bianchi EN, Grundberg E, Liang L, Richards JB, Estrada K, Zhou Y, van NA, Moffatt MF, Zhai G, Hofman A, van Meurs JB, Pols HA, Price RI, Nilsson O, Pastinen T, Cupples LA, Lusis AJ, Schadt EE, Ferrari S, Uitterlinden AG, Rivadeneira F, Spector TD, Karasik D, Kiel DP (2010) An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility loci for osteoporosis-related traits. PLoS Genet 6:e1000977. doi: 10.1371/journal.pgen.1000977
55. Duncan EL, Danoy P, Kemp JP, Leo PJ, McCloskey E, Nicholson GC, Eastell R, Prince RL, Eisman JA, Jones G, Sambrook PN, Reid IR, Dennison EM, Wark J, Richards JB, Uitterlinden AG, Spector TD, Esapa C, Cox RD, Brown SD, Thakker RV, Addison KA, Bradbury LA, Center JR, Cooper C, Cremin C, Estrada K, Felsenberg D, Gluer CC, Hadler J, Henry MJ, Hofman A, Kotowicz MA, Makovey J, Nguyen SC, Nguyen TV, Pasco JA, Pryce K, Reid DM, Rivadeneira F, Roux C, Stefansson K, Styrkarsdottir U, Thorleifsson G, Tichawangana R, Evans DM, Brown MA (2011) Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet 7:e1001372. doi: 10.1371/journal.pgen.1001372
56. Estrada K, Styrkarsdottir U, Evangelou E, Hsu YH, Duncan EL, Ntzani EE, Oei L, Albagha OM, Amin N, Kemp JP, Koller DL, Li G, Liu CT, Minster RL, Moayyeri A, Vandenput L, Willner D, Xiao SM, Yerges-Armstrong LM, Zheng HF, Alonso N, Eriksson J, Kammerer CM, Kaptoge SK, Leo PJ, Thorleifsson G, Wilson SG, Wilson JF, Aalto V, Alen M, Aragaki AK, Aspelund T, Center JR, Dailiana Z, Duggan DJ, Garcia M, Garcia-Giralt N, Giroux S, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Khusainova R, Kim GS, Kooperberg C, Koromila T, Kruk M, Laaksonen M, Lacroix AZ, Lee SH, Leung PC, Lewis JR, Masi L, Mencej-Bedrac S, Nguyen TV, Nogues X, Patel MS, Prezelj J, Rose LM, Scollen S, Siggeirsdottir K, Smith AV, Svensson O, Trompet S, Trummer O, van Schoor NM, Woo J, Zhu K, Balcells S, Brandi ML, Buckley BM, Cheng S, Christiansen C, Cooper C, Dedoussis G, Ford I, Frost M, Goltzman D, Gonzalez-Macias J, Kahonen M, Karlsson M, Khusnutdinova E, Koh JM, Kollia P, Langdahl BL, Leslie WD, Lips P, Ljunggren O, Lorenc RS, Marc J, Mellstrom D, Obermayer-Pietsch B, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Ridker PM, Rousseau F, Slagboom PE, Tang NL, Urreizti R, Van HW, Viikari J, Zarrabeitia MT, Aulchenko YS, Castano-Betancourt M, Grundberg E, Herrera L, Ingvarsson T, Johannsdottir H, Kwan T, Li R, Luben R, Medina-Gomez C, Palsson ST, Reppe S, Rotter JI, Sigurdsson G, van Meurs JB, Verlaan D, Williams FM, Wood AR, Zhou Y, Gautvik KM, Pastinen T, Raychaudhuri S, Cauley JA, Chasman DI, Clark GR, Cummings SR, Danoy P, Dennison EM, Eastell R, Eisman JA, Gudnason V, Hofman A, Jackson RD, Jones G, Jukema JW, Khaw KT, Lehtimaki T, Liu Y, Lorentzon M, McCloskey E, Mitchell BD, Nandakumar K, Nicholson GC, Oostra BA, Peacock M, Pols HA, Prince RL, Raitakari O, Reid IR, Robbins J, Sambrook PN, Sham PC, Shuldiner AR, Tylavsky FA, van Duijn CM, Wareham NJ, Cupples LA, Econs MJ, Evans DM, Harris TB, Kung AW, Psaty BM, Reeve J, Spector TD, Streeten EA, Zillikens MC, Thorsteinsdottir U, Ohlsson C, Karasik D, Richards JB, Brown MA, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JP, Kiel DP, Rivadeneira F (2012) Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet 44:491-501. doi: 10.1038/ng.2249
57. Zheng HF, Tobias JH, Duncan E, Evans DM, Eriksson J, Paternoster L, Yerges-Armstrong LM, Lehtimaki T, Bergstrom U, Kahonen M, Leo PJ, Raitakari O, Laaksonen M, Nicholson GC, Viikari J, Ladouceur M, Lyytikainen LP, Medina-Gomez C, Rivadeneira F, Prince RL, Sievanen H, Leslie WD, Mellstrom D, Eisman JA, Moverare-Skrtic S, Goltzman D, Hanley DA, Jones G, St PB, Xiao Y, Timpson NJ, Smith GD, Reid IR, Ring SM, Sambrook PN, Karlsson M, Dennison EM, Kemp JP, Danoy P, Sayers A, Wilson SG, Nethander M, McCloskey E, Vandenput L, Eastell R, Liu J, Spector T, Mitchell BD, Streeten EA, Brommage R, Pettersson-Kymmer U, Brown MA, Ohlsson C, Richards JB, Lorentzon M (2012) WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. PLoS Genet 8:e1002745. doi: 10.1371/journal.pgen.1002745
58. Medina-Gomez C, Kemp JP, Estrada K, Eriksson J, Liu J, Reppe S, Evans DM, Heppe DH, Vandenput L, Herrera L, Ring SM, Kruithof CJ, Timpson NJ, Zillikens MC, Olstad OK, Zheng HF, Richards JB, St PB, Hofman A, Jaddoe VW, Smith GD, Lorentzon M, Gautvik KM, Uitterlinden AG, Brommage R, Ohlsson C, Tobias JH, Rivadeneira F (2012) Meta-analysis of genome-wide scans for total body BMD in children and adults reveals allelic heterogeneity and age-specific effects at the WNT16 locus. PLoS Genet 8:e1002718. doi: 10.1371/journal.pgen.1002718
59. Koller DL, Zheng HF, Karasik D, Yerges-Armstrong L, Liu CT, McGuigan F, Kemp JP, Giroux S, Lai D, Edenberg HJ, Peacock M, Czerwinski SA, Choh AC, McMahon G, St PB, Timpson NJ, Lawlor DA, Evans DM, Towne B, Blangero J, Carless MA, Kammerer C, Goltzman D, Kovacs CS, Prior JC, Spector TD, Rousseau F, Tobias JH, Akesson K, Econs MJ, Mitchell BD, Richards JB, Kiel DP, Foroud T (2013) Meta-analysis of genome-wide studies identifies WNT16 and ESR1 SNPs associated with bone mineral density in premenopausal women. J Bone Miner Res 28:547-558. doi: 10.1002/jbmr.1796
60. Zhang L, Choi HJ, Estrada K, Leo PJ, Li J, Pei YF, Zhang Y, Lin Y, Shen H, Liu YZ, Liu Y, Zhao Y, Zhang JG, Tian Q, Wang YP, Han Y, Ran S, Hai R, Zhu XZ, Wu S, Yan H, Liu X, Yang TL, Guo Y, Zhang F, Guo YF, Chen Y, Chen X, Tan L, Zhang L, Deng FY, Deng H, Rivadeneira F, Duncan EL, Lee JY, Han BG, Cho NH, Nicholson GC, McCloskey E, Eastell R, Prince RL, Eisman JA, Jones G, Reid IR, Sambrook PN, Dennison EM, Danoy P, Yerges-Armstrong LM, Streeten EA, Hu T, Xiang S, Papasian CJ, Brown MA, Shin CS, Uitterlinden AG, Deng HW (2014) Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. Hum Mol Genet 23:1923-1933. doi: 10.1093/hmg/ddt575
61. Moayyeri A, Hsu YH, Karasik D, Estrada K, Xiao SM, Nielson C, Srikanth P, Giroux S, Wilson SG, Zheng HF, Smith AV, Pye SR, Leo PJ, Teumer A, Hwang JY, Ohlsson C, McGuigan F, Minster RL, Hayward C, Olmos JM, Lyytikainen LP, Lewis JR, Swart KM, Masi L, Oldmeadow C, Holliday EG, Cheng S, van Schoor NM, Harvey NC, Kruk M, Del Greco MF, Igl W, Trummer O, Grigoriou E, Luben R, Liu CT, Zhou Y, Oei L, Medina-Gomez C, Zmuda J, Tranah G, Brown SJ, Williams FM, Soranzo N, Jakobsdottir J, Siggeirsdottir K, Holliday KL, Hannemann A, Go MJ, Garcia M, Polasek O, Laaksonen M, Zhu K, Enneman AW, McEvoy M, Peel R, Sham PC, Jaworski M, Johansson A, Hicks AA, Pludowski P, Scott R, Dhonukshe-Rutten RA, van d, V, Kahonen M, Viikari JS, Sievanen H, Raitakari OT, Gonzalez-Macias J, Hernandez JL, Mellstrom D, Ljunggren O, Cho YS, Volker U, Nauck M, Homuth G, Volzke H, Haring R, Brown MA, McCloskey E, Nicholson GC, Eastell R, Eisman JA, Jones G, Reid IR, Dennison EM, Wark J, Boonen S, Vanderschueren D, Wu FC, Aspelund T, Richards JB, Bauer D, Hofman A, Khaw KT, Dedoussis G, Obermayer-Pietsch B, Gyllensten U, Pramstaller PP, Lorenc RS, Cooper C, Kung AW, Lips P, Alen M, Attia J, Brandi ML, de Groot LC, Lehtimaki T, Riancho JA, Campbell H, Liu Y, Harris TB, Akesson K, Karlsson M, Lee JY, Wallaschofski H, Duncan EL, O'Neill TW, Gudnason V, Spector TD, Rousseau F, Orwoll E, Cummings SR, Wareham NJ, Rivadeneira F, Uitterlinden AG, Prince RL, Kiel DP, Reeve J, Kaptoge SK (2014) Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. Hum Mol Genet 23:3054-3068 doi: 10.1093/hmg/ddt675
62. Mao J, Wang J, Liu B, Pan W, Farr GH III, Flynn C, Yuan H, Takada S, Kimelman D, Li L, Wu D (2001) Low-density lipoprotein receptor-related protein-5 binds to axin and regulates the canonical Wnt signaling pathway. Mol Cell 7:801-809
63. Logan CY, Nusse R (2004) The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol 20:781-810. doi: 10.1146/annurev.cellbio.20.010403.113126
64. Oei L, Hsu YH, Styrkarsdottir U, Eussen BH, de KA, Peters MJ, Halldorsson B, Liu CT, Alonso N, Kaptoge SK, Thorleifsson G, Hallmans G, Hocking LJ, Husted LB, Jameson KA, Kruk M, Lewis JR, Patel MS, Scollen S, Svensson O, Trompet S, van Schoor NM, Zhu K, Buckley BM, Cooper C, Ford I, Goltzman D, Gonzalez-Macias J, Langdahl BL, Leslie WD, Lips P, Lorenc RS, Olmos JM, Pettersson-Kymmer U, Reid DM, Riancho JA, Slagboom PE, Garcia-Ibarbia C, Ingvarsson T, Johannsdottir H, Luben R, Medina-Gomez C, Arp P, Nandakumar K, Palsson ST, Sigurdsson G, van Meurs JB, Zhou Y, Hofman A, Jukema JW, Pols HA, Prince RL, Cupples LA, Marshall CR, Pinto D, Sato D, Scherer SW, Reeve J, Thorsteinsdottir U, Karasik D, Richards JB, Stefansson K, Uitterlinden AG, Ralston SH, Ioannidis JP, Kiel DP, Rivadeneira F, Estrada K (2014) A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. J Med Genet 51:122-131 doi: 10.1136/jmedgenet-2013-102064
65. Oei L, Estrada K, Duncan EL, Christiansen C, Liu CT, Langdahl BL, Obermayer-Pietsch B, Riancho JA, Prince RL, van Schoor NM, McCloskey E, Hsu YH, Evangelou E, Ntzani E, Evans DM, Alonso N, Husted LB, Valero C, Hernandez JL, Lewis JR, Kaptoge SK, Zhu K, Cupples LA, Medina-Gomez C, Vandenput L, Kim GS, Hun LS, Castano-Betancourt MC, Oei EH, Martinez J, Daroszewska A, van der Klift M, Mellstrom D, Herrera L, Karlsson MK, Hofman A, Ljunggren O, Pols HA, Stolk L, van Meurs JB, Ioannidis JP, Zillikens MC, Lips P, Karasik D, Uitterlinden AG, Styrkarsdottir U, Brown MA, Koh JM, Richards JB, Reeve J, Ohlsson C, Ralston SH, Kiel DP, Rivadeneira F (2014) Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone 59:20-27
66. Winnier GE, Hargett L, Hogan BL (1997) The winged helix transcription factor MFH1 is required for proliferation and patterning of paraxial mesoderm in the mouse embryo. Genes Dev 11:926-940
67. Wang J, Wang W, Li R, Li Y, Tian G, Goodman L, Fan W, Zhang J, Li J, Zhang J, Guo Y, Feng B, Li H, Lu Y, Fang X, Liang H, Du Z, Li D, Zhao Y, Hu Y, Yang Z, Zheng H, Hellmann I, Inouye M, Pool J, Yi X, Zhao J, Duan J, Zhou Y, Qin J, Ma L, Li G, Yang Z, Zhang G, Yang B, Yu C, Liang F, Li W, Li S, Li D, Ni P, Ruan J, Li Q, Zhu H, Liu D, Lu Z, Li N, Guo G, Zhang J, Ye J, Fang L, Hao Q, Chen Q, Liang Y, Su Y, San A, Ping C, Yang S, Chen F, Li L, Zhou K, Zheng H, Ren Y, Yang L, Gao Y, Yang G, Li Z, Feng X, Kristiansen K, Wong GK, Nielsen R, Durbin R, Bolund L, Zhang X, Li S, Yang H, Wang J (2008) The diploid genome sequence of an Asian individual. Nature 456:60-65. doi: 10.1038/nature07484
68. Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A, He W, Chen YJ, Makhijani V, Roth GT, Gomes X, Tartaro K, Niazi F, Turcotte CL, Irzyk GP, Lupski JR, Chinault C, Song XZ, Liu Y, Yuan Y, Nazareth L, Qin X, Muzny DM, Margulies M, Weinstock GM, Gibbs RA, Rothberg JM (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452:872-876. doi: 10.1038/nature06884
69. Yoon JK, Lee JS (2012) Cellular signaling and biological functions of R-spondins. Cell Signal 24:369-377. doi: 10.1016/j.cellsig.2011.09.023
70. Luo J, Zhou W, Zhou X, Li D, Weng J, Yi Z, Cho SG, Li C, Yi T, Wu X, Li XY, de CB, Hook M, Liu M (2009) Regulation of bone formation and remodeling by G-protein-coupled receptor 48. Development 136:2747-2756. doi: 10.1242/dev.033571
71. Mendive F, Laurent P, Van SG, Skarnes W, Pochet R, Vassart G (2006) Defective postnatal development of the male reproductive tract in LGR4 knockout mice. Dev Biol 290:421-434. doi: 10.1016/j.ydbio.2005.11.043
72. Mazerbourg S, Bouley DM, Sudo S, Klein CA, Zhang JV, Kawamura K, Goodrich LV, Rayburn H, Tessier-Lavigne M, Hsueh AJ (2004) Leucine-rich repeat-containing, G protein-coupled receptor 4 null mice exhibit intrauterine growth retardation associated with embryonic and perinatal lethality. Mol Endocrinol 18:2241-2254. doi: 10.1210/me.2004-0133
73. Fahiminiya S, Majewski J, Roughley P, Roschger P, Klaushofer K, Rauch F (2013) Whole-exome sequencing reveals a heterozygous LRP5 mutation in a 6-year-old boy with vertebral compression fractures and low trabecular bone density. Bone 57:41-46. doi: 10.1016/j.bone.2013.07.020
74. Kruk M, Ralston SH, Albagha OM (2009) LRP5 polymorphisms and response to risedronate treatment in osteoporotic men. Calcif Tissue Int 84:171-179. doi: 10.1007/s00223-008-9207-5
75. Qureshi AM, Herd RJ, Blake GM, Fogelman I, Ralston SH (2002) COLIA1 Sp1 polymorphism predicts response of femoral neck bone density to cyclical etidronate therapy. Calcif Tissue Int 70:158-163. doi: 10.1007/s00223-001-1035-9
76. Tirabassi G, Delli MN, Gioia A, Biagioli A, Lenzi A, Balercia G (2014) Effects of testosterone replacement therapy on bone metabolism in male post-surgical hypogonadotropic hypogonadism: focus on the role of androgen receptor CAG polymorphism. J Endocrinol Invest doi: 10.1007/s40618-014-0052-2
77. Pirmohamed M, Burnside G, Eriksson N, Jorgensen AL, Toh CH, Nicholson T, Kesteven P, Christersson C, Wahlstrom B, Stafberg C, Zhang JE, Leathart JB, Kohnke H, Maitland-van der Zee AH, Williamson PR, Daly AK, Avery P, Kamali F, Wadelius M (2013) A randomized trial of genotype-guided dosing of warfarin. N Engl J Med 369:2294-2303. doi: 10.1056/NEJMoa1311386