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Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2.
- Source :
-
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research [J Bone Miner Res] 2016 Dec; Vol. 31 (12), pp. 2085-2097. Date of Electronic Publication: 2016 Sep 06. - Publication Year :
- 2016
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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 <superscript>-8</superscript> ) 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 <superscript>-10</superscript> ) and decreased risk of clinical vertebral fracture (OR = 0.82; FDR p = 7.4 × 10 <superscript>-4</superscript> ). 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 <superscript>-3</superscript> , 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.<br /> (© 2016 American Society for Bone and Mineral Research.)
- Subjects :
- Animals
Biopsy
Cancellous Bone diagnostic imaging
Cancellous Bone pathology
Cancellous Bone physiopathology
Excitatory Amino Acid Transporter 1 metabolism
Gene Expression Regulation
Humans
Linkage Disequilibrium genetics
Lumbar Vertebrae diagnostic imaging
Lumbar Vertebrae pathology
Lumbar Vertebrae physiopathology
Mice
Molecular Sequence Annotation
Organ Size
Osteoblasts metabolism
Quantitative Trait Loci genetics
Receptor, EphB2 metabolism
Risk Factors
Spinal Fractures diagnostic imaging
Spinal Fractures pathology
Spinal Fractures physiopathology
Spine diagnostic imaging
Bone Density genetics
Excitatory Amino Acid Transporter 1 genetics
Genetic Association Studies
Genetic Predisposition to Disease
Polymorphism, Single Nucleotide genetics
Receptor, EphB2 genetics
Spinal Fractures genetics
Spine pathology
Subjects
Details
- Language :
- English
- ISSN :
- 1523-4681
- Volume :
- 31
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
- Publication Type :
- Academic Journal
- Accession number :
- 27476799
- Full Text :
- https://doi.org/10.1002/jbmr.2913