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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD,Reduced Vertebral Fracture Risk,and Increased Expression of SLC1A3 and EPHB2
Authors:Carrie M Nielson  Ching‐Ti Liu  Albert V Smith  Cheryl L Ackert‐Bicknell  Sjur Reppe  Johanna Jakobsdottir  Christina Wassel  Thomas C Register  Ling Oei  Nerea Alonso  Edwin H Oei  Neeta Parimi  Elizabeth J Samelson  Mike A Nalls  Joseph Zmuda  Thomas Lang  Mary Bouxsein  Jeanne Latourelle  Melina Claussnitzer  Kristin Siggeirsdottir  Priya Srikanth  Erik Lorentzen  Liesbeth Vandenput  Carl Langefeld  Laura Raffield  Greg Terry  Amanda J Cox  Matthew A Allison  Michael H Criqui  Don Bowden  M Arfan Ikram  Dan Mellström  Magnus K Karlsson  John Carr  Matthew Budoff  Caroline Phillips  L Adrienne Cupples  Wen‐Chi Chou  Richard H Myers  Stuart H Ralston  Kaare M Gautvik  Peggy M Cawthon  Steven Cummings  David Karasik  Fernando Rivadeneira  Vilmundur Gudnason  Eric S Orwoll  Tamara B Harris  Claes Ohlsson  Douglas P Kiel  Yi‐Hsiang Hsu
Affiliation:1. School of Public Health, Oregon Health & Science University, Portland, OR, USACMN, DPK, and Y‐HH contributed equally to this work.;2. Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA;3. Icelandic Heart Association, Kópavogur, Iceland;4. Faculty of Medicine, University of Iceland, Reykjavík, Iceland;5. Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, NY, USA;6. Department of Medical Biochemistry, Oslo University Hospital, Ullev?l, Oslo, Norway;7. Lovisenberg Diakonale Hospital, Oslo, Norway;8. Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway;9. Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA;10. Department of Pathology, Wake Forest School of Medicine, Winston‐Salem, NC, USA;11. Internal Medicine, Erasmus MC, Rotterdam, The Netherlands;12. Netherlands Genomics Initiative (NGI)‐sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands;13. Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK;14. Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands;15. California Pacific Medical Center Research Institute, San Francisco, CA, USA;16. Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA;17. National Institute on Aging (NIA), National Institutes of Health, Bethesda, MD, USA;18. Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA;19. Department of Radiology, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA;20. Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA;21. Department of Neurology, Boston University, Boston, MA, USA;22. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA;23. Broad Institute of MIT and Harvard, Cambridge, MA, USA;24. Technical University Munich, Munich, Germany;25. Imaging, Icelandic Heart Association, Kópavogur, Iceland;26. School of Public Health, Oregon Health & Science University, Portland, OR, USA;27. Department of Bioinformatics, Gothenburg University, Gothenburg, Sweden;28. Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;29. Public Health Sciences, Wake Forest School of Medicine, Winston‐Salem, NC, USA;30. Center for Human Genomics, Wake Forest School of Medicine, Winston‐Salem, NC, USA;31. Center for Diabetes Research, Wake Forest School of Medicine, Winston‐Salem, NC, USA;32. Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA;33. Center for Diabetes Research, Department of Biochemistry, Wake Forest School of Medicine, Winston‐Salem, NC, USA;34. Department of Family Medicine and Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA;35. Internal Medicine/Endocrinology, Wake Forest School of Medicine, Winston‐Salem, NC, USA;36. Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston‐Salem, NC, USA;37. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands;38. Department of Orthopaedics and Clinical Sciences, Malm? University Hospital, Lund University, Malm?, Sweden;39. Los Angeles Biomedical Research Institute, Torrance, CA, USA;40. Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK;41. Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA;42. Faculty of Medicine in the Galilee, Bar‐Ilan University, Safed, Israel;43. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands;44. Division of Endocrinology, Oregon Health & Science University, Portland, OR, USA;45. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USACMN, DPK, and Y‐HH contributed equally to this work.;46. Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USACMN, DPK, and Y‐HH contributed equally to this work.
Abstract:Genome‐wide association studies (GWASs) have revealed numerous loci for areal bone mineral density (aBMD). We completed the first GWAS meta‐analysis (n = 15,275) of lumbar spine volumetric BMD (vBMD) measured by quantitative computed tomography (QCT), allowing for examination of the trabecular bone compartment. SNPs that were significantly associated with vBMD were also examined in two GWAS meta‐analyses to determine associations with morphometric vertebral fracture (n = 21,701) and clinical vertebral fracture (n = 5893). Expression quantitative trait locus (eQTL) analyses of iliac crest biopsies were performed in 84 postmenopausal women, and murine osteoblast expression of genes implicated by eQTL or by proximity to vBMD‐associated SNPs was examined. We identified significant vBMD associations with five loci, including: 1p36.12, containing WNT4 and ZBTB40; 8q24, containing TNFRSF11B; and 13q14, containing AKAP11 and TNFSF11. Two loci (5p13 and 1p36.12) also contained associations with radiographic and clinical vertebral fracture, respectively. In 5p13, rs2468531 (minor allele frequency [MAF] = 3%) was associated with higher vBMD (β = 0.22, p = 1.9 × 10–8) and decreased risk of radiographic vertebral fracture (odds ratio [OR] = 0.75; false discovery rate [FDR] p = 0.01). In 1p36.12, rs12742784 (MAF = 21%) was associated with higher vBMD (β = 0.09, p = 1.2 × 10–10) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10–4). Both SNPs are noncoding and were associated with increased mRNA expression levels in human bone biopsies: rs2468531 with SLC1A3 (β = 0.28, FDR p = 0.01, involved in glutamate signaling and osteogenic response to mechanical loading) and rs12742784 with EPHB2 (β = 0.12, FDR p = 1.7 × 10–3, functions in bone‐related ephrin signaling). Both genes are expressed in murine osteoblasts. This is the first study to link SLC1A3 and EPHB2 to clinically relevant vertebral osteoporosis phenotypes. These results may help elucidate vertebral bone biology and novel approaches to reducing vertebral fracture incidence. © 2016 American Society for Bone and Mineral Research.
Keywords:BONE QCT/μ  CT  ANALYSIS/QUANTITATION OF BONE  OSTEOPOROSIS  DISEASES AND DISORDERS OF/RELATED TO BONE  GENERAL POPULATION STUDIES  EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES  GENETIC RESEARCH  FRACTURE RISK ASSESSMENT
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