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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 Alonso, Nerea
Nielson, Carrie M.
Liu, Ching-Ti
Smith, Albert V.
Ackert-Bicknell, Cheryl L.
Reppe, Sjur
Jakobsdottir, Johanna
Wassel, Christina
Register, Thomas C.
Oei, Ling
Alonso, Nerea
Author
Nielson, Carrie M.
Liu, Ching-Ti
Smith, Albert V.
Ackert-Bicknell, Cheryl L.
Reppe, Sjur
Jakobsdottir, Johanna
Wassel, Christina
Register, Thomas C.
Oei, Ling
Alonso, Nerea
Oei, Edwin H.
Parimi, Neeta
Samelson, Elizabeth J.
Nalls, Mike A.
Zmuda, Joseph
Lang, Thomas
Bouxsein, Mary
Latourelle, Jeanne
Claussnitzer, Melina
Siggeirsdottir, Kristin
Srikanth, Priya
Lorentzen, Erik
Vandenput, Liesbeth
Langefeld, Carl D.
Raffield, Laura
Terry, Greg
Cox, Amanda J.
Allison, Matthew A.
Criqui, Michael H.
Bowden, Don
Ikram, M. Arfan
Mellström, Dan
Karlsson, Magnus K.
Carr, John
Budoff, Matthew
Phillips, Caroline
Cupples, L. Adrienne
Chou, Wen-Chi
Myers, Richard H.
Ralston, Stuart H.
Gautvik, Kaare M.
Cawthon, Peggy M.
Cummings, Steven
Karasik, David
Rivadeneira, Fernando
Gudnason, Vilmundur
Orwoll, Eric S.
Harris, Tamara B.
Ohlsson, Claes
Kiel, Douglas P.
Hsu, Yi-Hsiang
Liu, Ching-Ti
Smith, Albert V.
Ackert-Bicknell, Cheryl L.
Reppe, Sjur
Jakobsdottir, Johanna
Wassel, Christina
Register, Thomas C.
Oei, Ling
Alonso, Nerea
Oei, Edwin H.
Parimi, Neeta
Samelson, Elizabeth J.
Nalls, Mike A.
Zmuda, Joseph
Lang, Thomas
Bouxsein, Mary
Latourelle, Jeanne
Claussnitzer, Melina
Siggeirsdottir, Kristin
Srikanth, Priya
Lorentzen, Erik
Vandenput, Liesbeth
Langefeld, Carl D.
Raffield, Laura
Terry, Greg
Cox, Amanda J.
Allison, Matthew A.
Criqui, Michael H.
Bowden, Don
Ikram, M. Arfan
Mellström, Dan
Karlsson, Magnus K.
Carr, John
Budoff, Matthew
Phillips, Caroline
Cupples, L. Adrienne
Chou, Wen-Chi
Myers, Richard H.
Ralston, Stuart H.
Gautvik, Kaare M.
Cawthon, Peggy M.
Cummings, Steven
Karasik, David
Rivadeneira, Fernando
Gudnason, Vilmundur
Orwoll, Eric S.
Harris, Tamara B.
Ohlsson, Claes
Kiel, Douglas P.
Hsu, Yi-Hsiang
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.
Keywords
bone QCT/mCT, analysis/quantitation of bone, osteoporosis, diseases and disorders of/related to bone, generalpopulation studies, epidemiology, human association studies, genetic research, fracture risk assessment
Date
2016
Type
Journal article
Journal
Journal of Bone and Mineral Research
Book
Volume
31
Issue
12
Page Range
2085-2097
Article Number
ACU Department
Mary MacKillop Institute for Health Research
Faculty of Health Sciences
Faculty of Health Sciences
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Relation URI
Source URL
Event URL
Open Access Status
License
File Access
Controlled