Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2

Journal of Bone and Mineral Research

Volumn 31, Issue 12, 2016, Pages 2085-2097

  Nielson, Carrie M ^a   Liu, Ching Ti ^b   Smith, Albert V ^c,d   Ackert Bicknell, Cheryl L ^e   Reppe, Sjur ^f,g,h   Jakobsdottir, Johanna ^c   Wassel, Christina ⁱ   Register, Thomas C ^j   Oei, Ling ^k,l   Alonso, Nerea ^m   Oei, Edwin H ^k   Parimi, Neeta ⁿ   Samelson, Elizabeth J ^o   Nalls, Mike A ^p   Zmuda, Joseph ^q   Lang, Thomas ^r   Bouxsein, Mary ^o   Latourelle, Jeanne ^s   Claussnitzer, Melina ^o,t,u   Siggeirsdottir, Kristin ^c   Srikanth, Priya ^a   Lorentzen, Erik ^v   Vandenput, Liesbeth ^w   Langefeld, Carl ^j   Raffield, Laura ^j   Terry, Greg ^x   Cox, Amanda J ^j   Allison, Matthew A ^y   Criqui, Michael H ^y   Bowden, Don ^j   Ikram, M Arfan ^k   Mellström, Dan ^w   Karlsson, Magnus K ^z   Carr, John ^x   Budoff, Matthew ^aa   Phillips, Caroline ^p   Cupples, L Adrienne ^b   Chou, Wen Chi ^t   Myers, Richard H ^s   Ralston, Stuart H ^m   Gautvik, Kaare M ^g,h   Cawthon, Peggy M ^n,r   Cummings, Steven ⁿ   Karasik, David ^o,ab   Rivadeneira, Fernando ^k   Gudnason, Vilmundur ^c,d   Orwoll, Eric S ^ac   Harris, Tamara B ^p   Ohlsson, Claes ^w   Kiel, Douglas P ^o   Hsu, Yi Hsiang ^o,t,ad   more..

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH   (United States)

^c ICELANDIC HEART ASSOCIATION   (Iceland)

^d UNIVERSITY OF ICELAND   (Iceland)

^e UNIVERSITY OF ROCHESTER   (United States)

^f ULLEVÅL UNIVERSITY HOSPITAL   (Norway)

^g LOVISENBERG DIAKONALE HOSPITAL   (Norway)

^h UNIVERSITY OF OSLO   (Norway)

ⁱ UNIVERSITY OF VERMONT COLLEGE OF MEDICINE   (United States)

^j WAKE FOREST SCHOOL OF MEDICINE   (United States)

^k ERASMUS MEDICAL CENTER   (Netherlands)

^l Netherlands Genomics Initiative   (Netherlands)

^m UNIVERSITY OF EDINBURGH   (United Kingdom)

ⁿ CALIFORNIA PACIFIC MEDICAL CENTER   (United States)

^o HARVARD MEDICAL SCHOOL   (United States)

^p NATIONAL INSTITUTE ON AGING   (United States)

^q UNIVERSITY OF PITTSBURGH GRADUATE SCHOOL OF PUBLIC HEALTH   (United States)

^r UNIVERSITY OF CALIFORNIA   (United States)

^s BOSTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

^t BROAD INSTITUTE OF MIT AND HARVARD   (United States)

^u TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^v UNIVERSITY OF GOTHENBURG   (Sweden)

^w UNIVERSITY OF GOTHENBURG   (Sweden)

^x VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^y UNIVERSITY OF CALIFORNIA   (United States)

^z LUND UNIVERSITY HOSPITAL   (Sweden)

^aa LOS ANGELES BIOMEDICAL RESEARCH INSTITUTE   (United States)

^ab BAR ILAN UNIVERSITY   (Israel)

^ac OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^ad HARVARD SCHOOL OF PUBLIC HEALTH   (United States)

more..

Author keywords

ANALYSIS QUANTITATION OF BONE; BONE QCT CT; DISEASES AND DISORDERS OF RELATED TO BONE; EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES; FRACTURE RISK ASSESSMENT; GENERAL POPULATION STUDIES; GENETIC RESEARCH; OSTEOPOROSIS

Indexed keywords

EPHRIN; EPHRIN RECEPTOR B2; EXCITATORY AMINO ACID TRANSPORTER 1; GLUTAMIC ACID; OSTEOPROTEGERIN; WNT4 PROTEIN; EPHB2 PROTEIN, HUMAN; SLC1A3 PROTEIN, HUMAN;

ADULT; AGED; ANIMAL CELL; ARTICLE; BONE DENSITY; BONE DEVELOPMENT; BONE MARROW BIOPSY; BONE MASS; BONE MICROARCHITECTURE; CLINICAL ARTICLE; COHORT ANALYSIS; COMPUTER ASSISTED TOMOGRAPHY; FEMALE; GENE; GENE EXPRESSION; GENE FREQUENCY; GENE LOCUS; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENOTYPE; GREM2 GENE; HUMAN; HUMAN CELL; HUMAN TISSUE; LUMBAR SPINE; MALE; MOUSE; NONHUMAN; OSTEOBLAST; OSTEOPOROSIS; PHENOTYPE; POSTMENOPAUSE; QUANTITATIVE ANALYSIS; QUANTITATIVE TRAIT LOCUS; RISK ASSESSMENT; RISK REDUCTION; SIGNAL TRANSDUCTION; SINGLE NUCLEOTIDE POLYMORPHISM; SPINE FRACTURE; TRABECULAR BONE; WNT SIGNALING PATHWAY; ZBTB40 GENE; ANIMAL; BIOPSY; DIAGNOSTIC IMAGING; GENE EXPRESSION REGULATION; GENE LINKAGE DISEQUILIBRIUM; GENETIC ASSOCIATION STUDY; GENETIC PREDISPOSITION; GENETICS; LUMBAR VERTEBRA; METABOLISM; MOLECULAR GENETICS; ORGAN SIZE; PATHOLOGY; PATHOPHYSIOLOGY; RISK FACTOR; SPINE;

ANIMALS; BIOPSY; BONE DENSITY; CANCELLOUS BONE; EXCITATORY AMINO ACID TRANSPORTER 1; GENE EXPRESSION REGULATION; GENETIC ASSOCIATION STUDIES; GENETIC PREDISPOSITION TO DISEASE; HUMANS; LINKAGE DISEQUILIBRIUM; LUMBAR VERTEBRAE; MICE; MOLECULAR SEQUENCE ANNOTATION; ORGAN SIZE; OSTEOBLASTS; POLYMORPHISM, SINGLE NUCLEOTIDE; QUANTITATIVE TRAIT LOCI; RECEPTOR, EPHB2; RISK FACTORS; SPINAL FRACTURES; SPINE;

EID: 84992603238     PISSN: 08840431     EISSN: 15234681     Source Type: Journal    
DOI: 10.1002/jbmr.2913     Document Type: Article

References (58)

1. Kendler DL, Bauer DC, Davison KS, et al. Vertebral fractures: clinical importance and management. Am J Med. 2015; 129(2):221.e1–e10.
2. Oudshoorn C, Hartholt KA, Zillikens MC, et al. Emergency department visits due to vertebral fractures in the Netherlands, 1986-2008: steep increase in the oldest old, strong association with falls. Injury. 2012; 43(4):458–61.
3. Leslie WD, Sadatsafavi M, Lix LM, et al. Secular decreases in fracture rates 1986-2006 for Manitoba, Canada: a population-based analysis. Osteoporos Int. 2011; 22(7):2137–43.
4. Amin S, Achenbach SJ, Atkinson EJ, Khosla S, Melton LJ 3rd. Trends in fracture incidence: a population-based study over 20 years. J Bone Miner Res. 2014; 29(3):581–9.
5. Perilli E, Briggs AM, Kantor S, et al. Failure strength of human vertebrae: prediction using bone mineral density measured by DXA and bone volume by micro-CT. Bone. 2012; 50(6):1416–25.
6. Liu CT, Karasik D, Zhou Y, et al. Heritability of prevalent vertebral fracture and volumetric bone mineral density and geometry at the lumbar spine in three generations of the Framingham study. J Bone Miner Res. 2012; 27(4):954–8.
7. Richards JB, Zheng HF, Spector TD. Genetics of osteoporosis from genome-wide association studies: advances and challenges. Nat Rev Genet. 2012; 13(8):576–88.
8. Estrada K, Styrkarsdottir U, Evangelou E, et al. Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nat Genet. 2012; 44(5):491–501.
9. Oei L, Estrada K, Duncan EL, et al. Genome-wide association study for radiographic vertebral fractures: a potential role for the 16q24 BMD locus. Bone. 2014; 59:20–7.
10. Richards JB, Kavvoura FK, Rivadeneira F, et al. Genetic Factors for Osteoporosis Consortium. Collaborative meta-analysis: associations of 150 candidate genes with osteoporosis and osteoporotic fracture. Ann Intern Med. 2009; 151(8):528–37.
11. Anderson DE, Demissie S, Allaire BT, et al. The associations between QCT-based vertebral bone measurements and prevalent vertebral fractures depend on the spinal locations of both bone measurement and fracture. Osteoporos Int. 2014; 25(2):559–66.
12. Orwoll ES, Oviatt SK, Mann T. The impact of osteophytic and vascular calcifications on vertebral mineral density measurements in men. J Clin Endocrinol Metab. 1990; 70(4):1202–7.
13. Li N, Li XM, Xu L, Sun WJ, Cheng XG, Tian W. Comparison of QCT and DXA: osteoporosis detection rates in postmenopausal women. Int J Endocrinol. 2013; 2013:895474.
14. Harris TB, Launer LJ, Eiriksdottir G, et al. Age, Gene/Environment Susceptibility-Reykjavik Study: multidisciplinary applied phenomics. Am J Epidemiol. 2007; 165(9):1076–87.
15. Samelson EJ, Christiansen BA, Demissie S, et al. QCT measures of bone strength at the thoracic and lumbar spine: the Framingham Study. J Bone Miner Res. 2012; 27(3):654–63.
16. Budoff MJ, Hamirani YS, Gao YL, et al. Measurement of thoracic bone mineral density with quantitative CT. Radiology. 2010; 257(2):434–40.
17. Orwoll E, Blank JB, Barrett-Connor E, et al. Design and baseline characteristics of the osteoporotic fractures in men (MrOS) study—a large observational study of the determinants of fracture in older men. Contemp Clin Trials. 2005; 26(5):569–85.
18. Lang TF, Li J, Harris ST, Genant HK. Assessment of vertebral bone mineral density using volumetric quantitative CT. J Comput Assist Tomogr. 1999; 23(1):130–7.
19. Genant HK, Wu CY, van Kuijk C, Nevitt MC. Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res. 1993; 8(9):1137–48.
20. Black DM, Cummings SR, Stone K, Hudes E, Palermo L, Steiger P. A new approach to defining normal vertebral dimensions. J Bone Miner Res. 1991; 6(8):883–92.
21. Black DM, Palermo L, Nevitt MC, et al. Comparison of methods for defining prevalent vertebral deformities: the Study of Osteoporotic Fractures. J Bone Miner Res. 1995; 10(6):890–902.
22. Cawthon PM, Haslam J, Fullman R, et al. Osteoporotic Fractures in Men Research Group. Methods and reliability of radiographic vertebral fracture detection in older men: the osteoporotic fractures in men study. Bone. 2014; 67:152–5.
23. Alonso N, The Clinical Vertebral Fracture Consortium, Uitterlinden A, Rivadeneira F, Ralston SH. Identification of a novel locus on 2q13 of large effect size which predisposes to clinical vertebral fractures independently of BMD: the GEFOS Consortium. Bone Abstracts. 2016; 5:P241.
24. Lange LA, Burdon K, Langefeld CD, et al. Heritability and expression of C-reactive protein in type 2 diabetes in the Diabetes Heart Study. Ann Hum Genet. 2006; 70(Pt 6):717–25.
25. Hsu FC, Lenchik L, Nicklas BJ, et al. Heritability of body composition measured by DXA in the diabetes heart study. Obes Res. 2005; 13(2):312–9.
26. Yang B, Sun H, Wang H. The downstream effects of vitamin D in spermatozoa needs further study. Hum Reprod. 2010; 25(8):2152–3; author reply 2153.
27. Yang J, Lee SH, Goddard ME, Visscher PM. GCTA: a tool for genome-wide complex trait analysis. Am J Hum Genet. 2011; 88(1):76–82.
28. Reppe S, Refvem H, Gautvik VT, et al. Eight genes are highly associated with BMD variation in postmenopausal Caucasian women. Bone. 2010; 46(3):604–12.
29. Hsu YH, Zillikens MC, Wilson SG, et al. 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. 2010; 6(6):e1000977.
30. Zheng HF, Forgetta V, Hsu YH, et al. Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture. Nature. 2015; 526(7571):112–7.
31. ENCODE Project Consortium. The ENCODE (ENCyclopedia Of DNA Elements) project. Science. 2004; 306(5696):636–40.
32. Roadmap Epigenomics Consortium, Kundaje A, Meuleman W, et al. Integrative analysis of 111 reference human epigenomes. Nature. 2015; 518(7539):317–30.
33. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(Database issue):D930–4.
34. Ernst J, Kellis M. ChromHMM: automating chromatin-state discovery and characterization. Nat Methods. 2012; 9(3):215–6.
35. Reppe S, Wang Y, Thompson WK, et al. GEFOS Consortium. Genetic sharing with cardiovascular disease risk factors and diabetes reveals novel bone mineral density loci. PLoS One. 2015; 10(12):e0144531.
36. Duncan EL, Danoy P, Kemp JP, et al. Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. PLoS Genet. 2011; 7(4):e1001372.
37. Karasik D, Myers RH, Hannan MT, et al. Mapping of quantitative ultrasound of the calcaneus bone to chromosome 1 by genome-wide linkage analysis. Osteoporos Int. 2002; 13(10):796–802.
38. Styrkarsdottir U, Halldorsson BV, Gretarsdottir S, et al. Multiple genetic loci for bone mineral density and fractures. N Engl J Med. 2008; 358(22):2355–65.
39. Brakspear KS, Mason DJ. Glutamate signaling in bone. Front Endocrinol (Lausanne). 2012; 3:97.
40. Mason DJ, Suva LJ, Genever PG, et al. Mechanically regulated expression of a neural glutamate transporter in bone: a role for excitatory amino acids as osteotropic agents? Bone. 1997; 20(3):199–205.
41. Gray C, Marie H, Arora M, et al. Glutamate does not play a major role in controlling bone growth. J Bone Miner Res. 2001; 16(4):742–9.
42. Schraven SP, Franz C, Ruttiger L, et al. Altered phenotype of the vestibular organ in GLAST-1 null mice. J Assoc Res Otolaryngol. 2012; 13(3):323–33.
43. Courtland HW, Elis S, Wu Y, et al. Serum IGF-1 affects skeletal acquisition in a temporal and compartment-specific manner. PLoS One. 2011; 6(3):e14762.
44. Sabsovich I, Clark JD, Liao G, et al. Bone microstructure and its associated genetic variability in 12 inbred mouse strains: microCT study and in silico genome scan. Bone. 2008; 42(2):439–51.
45. Zanotti S, Canalis E. Activation of Nfatc2 in osteoblasts causes osteopenia. J Cell Physiol. 2015; 230(7):1689–95.
46. Raft S, Coate TM, Kelley MW, Crenshaw EB 3rd, Wu DK. Pou3f4-mediated regulation of ephrin-b2 controls temporal bone development in the mouse. PLoS One. 2014; 9(10):e109043.
47. Zhao C, Irie N, Takada Y, et al. Bidirectional ephrinB2-EphB4 signaling controls bone homeostasis. Cell Metab. 2006; 4(2):111–21.
48. Zhu L, Dissanayaka WL, Green DW, Zhang C. Stimulation of EphB2/ephrin-B1 signalling by tumour necrosis factor alpha in human dental pulp stem cells. Cell Prolif. 2015; 48(2):231–8.
49. Takyar FM, Tonna S, Ho PW, et al. EphrinB2/EphB4 inhibition in the osteoblast lineage modifies the anabolic response to parathyroid hormone. J Bone Miner Res. 2013; 28(4):912–25.
50. Wang Y, Menendez A, Fong C, ElAlieh HZ, Chang W, Bikle DD. Ephrin B2/EphB4 mediates the actions of IGF-I signaling in regulating endochondral bone formation. J Bone Miner Res. 2014; 29(8):1900–13.
51. Paternoster L, Lorentzon M, Lehtimaki T, et al. Genetic determinants of trabecular and cortical volumetric bone mineral densities and bone microstructure. PLoS Genet. 2013; 9(2):e1003247.
52. Ackert-Bicknell CL, Karasik D, Li Q, et al. Mouse BMD quantitative trait loci show improved concordance with human genome-wide association loci when recalculated on a new, common mouse genetic map. J Bone Miner Res. 2010; 25(8):1808–20.
53. Ideno H, Takanabe R, Shimada A, et al. Protein related to DAN and cerberus (PRDC) inhibits osteoblastic differentiation and its suppression promotes osteogenesis in vitro. Exp Cell Res. 2009; 315(3):474–84.
54. Im J, Kim H, Kim S, Jho EH. Wnt/beta-catenin signaling regulates expression of PRDC, an antagonist of the BMP-4 signaling pathway. Biochem Biophys Res Commun. 2007; 354(1):296–301.
55. Suzuki D, Yamada A, Aizawa R, et al. BMP2 differentially regulates the expression of Gremlin1 and Gremlin2, the negative regulators of BMP function, during osteoblast differentiation. Calcif Tissue Int. 2012; 91(1):88–96.
56. Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med. 2013; 19(2):179–92.
57. Yu B, Chang J, Liu Y, et al. Wnt4 signaling prevents skeletal aging and inflammation by inhibiting nuclear factor-kappaB. Nat Med. 2014; 20(9):1009–17.
58. Zmuda JM, Yerges-Armstrong LM, Moffett SP, et al. Osteoporotic Fractures in Men Study Group. Genetic analysis of vertebral trabecular bone density and cross-sectional area in older men. Osteoporos Int. 2011; 22(4):1079–90.