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

Carrie M. Nielson(Oregon Health & Science University), Ching‐Ti Liu(Boston University), Albert V. Smith(University of Iceland), Cheryl L. Ackert‐Bicknell(University of Rochester), Sjur Reppe(University of Oslo), Jóhanna Jakobsdóttir(Icelandic Heart Association), Christina L. Wassel(University of Vermont), Thomas C. Register(Wake Forest University), Ling Oei(DSM (Netherlands)), Nerea Alonso(Institute of Genetics and Cancer), Edwin H. G. Oei(DSM (Netherlands)), Neeta Parimi(California Pacific Medical Center), Elizabeth J. Samelson(Harvard University), Mike A. Nalls(National Institutes of Health), Joseph M. Zmuda(University of Pittsburgh), Thomas Lang(University of California, San Francisco), Mary Bouxsein(Beth Israel Deaconess Medical Center), Jeanne C. Latourelle(Boston University), Melina Claussnitzer(Broad Institute), Kristín Siggeirsdóttir(Icelandic Heart Association), Priya Srikanth(Oregon Health & Science University), Erik Lorentzen(Carl von Ossietzky Universität Oldenburg), Liesbeth Vandenput(University of Gothenburg), Carl D. Langefeld(Wake Forest University), Laura M. Raffield(Wake Forest University), Greg Terry(Vanderbilt University Medical Center), Amanda J. Cox(Wake Forest University), Matthew Allison(UC San Diego Health System), Michael H. Criqui(UC San Diego Health System), D. W. Bowden(Wake Forest University), M. Arfan Ikram(DSM (Netherlands)), Dan Mellström(University of Gothenburg), Magnus K. Karlsson(Malmö University), J. Jeffrey Carr(Vanderbilt University Medical Center), Matthew J. Budoff(The Lundquist Institute), Caroline L. Phillips(National Institutes of Health), L. Adrienne Cupples(Boston University), Wen‐Chi Chou(Broad Institute), Richard H. Myers(Boston University), Stuart H. Ralston(Institute of Genetics and Cancer), Kaare M. Gautvik(University of Oslo), Peggy M. Cawthon(University of California, San Francisco), Steven R. Cummings(California Pacific Medical Center), David Karasik(Harvard University), Fernando Rivadeneira(DSM (Netherlands)), Vilmundur Guðnason(University of Iceland), Eric Orwoll(Oregon Health & Science University), Tamara B. Harris(National Institutes of Health), Claes Ohlsson(University of Gothenburg), Douglas P. Kiel(Beth Israel Deaconess Medical Center), Yi-Hsiang Hsu(Broad Institute)
Journal of Bone and Mineral Research
August 1, 2016
10.1002/jbmr.2913
Cited by 46Open Access
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Abstract

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.

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