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

Nielson, Carrie M.; Liu, Ching Ti; Smith, Albert V.; Ackert-Bicknell, Cheryl L.; Reppe, Sjur; Jakobsdottir, Johanna; Wassel, Christina; Register, Thomas C.; Oei, Ling and Alonso, Nerea, et al. (2016) In Journal of Bone and Mineral Research 31(12). p.2085-2097
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... (More)

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.

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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
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Journal of Bone and Mineral Research
volume
31
issue
12
pages
2085 - 2097
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AMBMR
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  • scopus:84992603238
  • wos:000389445100005
ISSN
0884-0431
DOI
10.1002/jbmr.2913
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English
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f8c025c9-929e-44a9-b7e0-a0653a09d212
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2016-11-21 13:46:08
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2017-11-14 09:51:57
@article{f8c025c9-929e-44a9-b7e0-a0653a09d212,
  abstract     = {<p>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<sup>-8</sup>) 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<sup>-10</sup>) and decreased risk of clinical vertebral fracture (OR=0.82; FDR p=7.4×10<sup>-4</sup>). 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<sup>-3</sup>, 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.</p>},
  author       = {Nielson, Carrie M. and Liu, Ching Ti and Smith, Albert V. and Ackert-Bicknell, Cheryl L. and Reppe, Sjur and Jakobsdottir, Johanna and Wassel, Christina and Register, Thomas C. and Oei, Ling and Alonso, Nerea and Oei, Edwin H. and Parimi, Neeta and Samelson, Elizabeth J. and Nalls, Mike A. and Zmuda, Joseph and Lang, Thomas and Bouxsein, Mary and Latourelle, Jeanne and Claussnitzer, Melina and Siggeirsdottir, Kristin and Srikanth, Priya and Lorentzen, Erik and Vandenput, Liesbeth and Langefeld, Carl and Raffield, Laura and Terry, Greg and Cox, Amanda J. and Allison, Matthew A. and Criqui, Michael H. and Bowden, Don and Ikram, M. Arfan and Mellström, Dan and Karlsson, Magnus K. and Carr, John and Budoff, Matthew and Phillips, Caroline and Cupples, L. Adrienne and Chou, Wen Chi and Myers, Richard H. and Ralston, Stuart H. and Gautvik, Kaare M. and Cawthon, Peggy M. and Cummings, Steven and Karasik, David and Rivadeneira, Fernando and Gudnason, Vilmundur and Orwoll, Eric S. and Harris, Tamara B. and Ohlsson, Claes and Kiel, Douglas P. and Hsu, Yi Hsiang},
  issn         = {0884-0431},
  keyword      = {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},
  language     = {eng},
  number       = {12},
  pages        = {2085--2097},
  publisher    = {AMBMR},
  series       = {Journal of Bone and Mineral Research},
  title        = {Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2},
  url          = {http://dx.doi.org/10.1002/jbmr.2913},
  volume       = {31},
  year         = {2016},
}