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

Journal article
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
Published in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Volume 31
Issue 12
Pages 2085-2097
ISSN 1523-4681
Publication year 2016
Published at Core Facilities, Bioinformatics
Centre for Bone and Arthritis Research
Institute of Medicine, Department of Internal Medicine and Clinical Nutrition
Pages 2085-2097
Language en
Links dx.doi.org/10.1002/jbmr.2913
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Endocrinology

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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