title: Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.
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.
authors.affiliation: School of Public Health, Oregon Health & Science University, Portland, OR, USA.
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authors.lastname: Nielson
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
authors.forename: Ching-Ti
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authors.lastname: Liu
authors.affiliation: Icelandic Heart Association, Kópavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
authors.forename: Albert V
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authors.lastname: Smith
authors.affiliation: Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, NY, USA.
authors.forename: Cheryl L
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authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway.|Lovisenberg Diakonale Hospital, Oslo, Norway.|Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
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authors.affiliation: Icelandic Heart Association, Kópavogur, Iceland.
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authors.affiliation: Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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authors.forename: Ling
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authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK.
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authors.affiliation: Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
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authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Technical University Munich, Munich, Germany.
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authors.affiliation: Department of Family Medicine and Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
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authors.initials: MH
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authors.affiliation: Center for Diabetes Research, Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Internal Medicine/Endocrinology, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
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authors.affiliation: Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA.
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authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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authors.initials: WC
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authors.affiliation: Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK.
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authors.affiliation: Lovisenberg Diakonale Hospital, Oslo, Norway.|Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
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authors.initials: KM
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authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, CA, USA.|Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
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authors.initials: PM
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authors.forename: David
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authors.affiliation: Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.|Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
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authors.affiliation: Icelandic Heart Association, Kópavogur, Iceland.|Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
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authors.initials: DP
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authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA.|Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA.
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mesh_terms: D000818:Animals; D001706:Biopsy; D015519:Bone Density / Q000235:genetics*; D000071556:Cancellous Bone / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D027341:Excitatory Amino Acid Transporter 1 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D058977:Molecular Sequence Annotation; D009929:Organ Size; D010006:Osteoblasts / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D036183:Receptor, EphB2 / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D016103:Spinal Fractures / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D013131:Spine / Q000000981:diagnostic imaging / Q000473:pathology*
chemical_list: D027341:Excitatory Amino Acid Transporter 1; C493394:SLC1A3 protein, human; C586310:EPHB2 protein, human; D036183:Receptor, EphB2
keywords: ANALYSIS/QUANTITATION OF BONE; BONE QCT/μCT; DISEASES AND DISORDERS OF/RELATED TO BONE; EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES; FRACTURE RISK ASSESSMENT; GENERAL POPULATION STUDIES; GENETIC RESEARCH; OSTEOPOROSIS