Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2

Carrie M Nielson; Ching-Ti Liu; Albert V Smith; Cheryl L Ackert-Bicknell; Sjur Reppe; Jakobsdottir Johanna; Christina Wassel; Thomas C Register; Ling Oei; Nerea Alonso Lopez; 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

doi:10.1002/jbmr.2913

Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2

Carrie M Nielson, Ching-Ti Liu, Albert V Smith, Cheryl L Ackert-Bicknell, Sjur Reppe, Jakobsdottir Johanna, Christina Wassel, Thomas C Register, Ling Oei, Nerea Alonso Lopez, Edwin H Oei, Neeta Parimi, Elizabeth J Samelson, Mike A Nalls, Joseph Zmuda, Thomas Lang, Mary Bouxsein, Jeanne Latourelle, Melina Claussnitzer, Kristin SiggeirsdottirPriya 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

Research output: Contribution to journal › Article › peer-review

Abstract

Genome-wide association studies (GWAS) 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 in (N = 21,701) and clinical vertebral fracture (N = 5,893). Expression QTL 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 (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 non-coding 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. This article is protected by copyright. All rights reserved.

Original language	English
Journal	Journal of Bone and Mineral Research
Volume	31
Issue number	12
Early online date	1 Aug 2016
DOIs	https://doi.org/10.1002/jbmr.2913
Publication status	Published - Dec 2016

Access to Document

10.1002/jbmr.2913

Nielson_et_al-2016-Journal_of_Bone_and_Mineral_Research
Author's final peer-reviewed manuscript as accepted for publication
Accepted author manuscript, 1.14 MB

Cite this

Nielson, C. M., Liu, C-T., Smith, A. V., Ackert-Bicknell, C. L., Reppe, S., Johanna, J., Wassel, C., Register, T. C., Oei, L., Alonso Lopez, N., Oei, E. H., Parimi, N., Samelson, E. J., Nalls, M. A., Zmuda, J., Lang, T., Bouxsein, M., Latourelle, J., Claussnitzer, M., ... Hsu, Y-H. (2016). Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2. Journal of Bone and Mineral Research, 31(12). https://doi.org/10.1002/jbmr.2913

@article{28f7e46ef5ac4bcc8a448cce0fb271c1,

title = "Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2",

abstract = "Genome-wide association studies (GWAS) 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 in (N = 21,701) and clinical vertebral fracture (N = 5,893). Expression QTL 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 (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 non-coding 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. This article is protected by copyright. All rights reserved.",

author = "Nielson, {Carrie M} and Ching-Ti Liu and Smith, {Albert V} and Ackert-Bicknell, {Cheryl L} and Sjur Reppe and Jakobsdottir Johanna and Christina Wassel and Register, {Thomas C} and Ling Oei and {Alonso Lopez}, Nerea and Oei, {Edwin H} and Neeta Parimi and Samelson, {Elizabeth J} and Nalls, {Mike A} and Joseph Zmuda and Thomas Lang and Mary Bouxsein and Jeanne Latourelle and Melina Claussnitzer and Kristin Siggeirsdottir and Priya Srikanth and Erik Lorentzen and Liesbeth Vandenput and Carl Langefeld and Laura Raffield and Greg Terry and Cox, {Amanda J} and Allison, {Matthew A} and Criqui, {Michael H} and Don Bowden and Ikram, {M Arfan} and Dan Mellstr{\"o}m and Karlsson, {Magnus K} and John Carr and Matthew Budoff and Caroline Phillips and Cupples, {L Adrienne} and Wen-Chi Chou and Myers, {Richard H} and Ralston, {Stuart H} and Gautvik, {Kaare M} and Cawthon, {Peggy M} and Steven Cummings and David Karasik and Fernando Rivadeneira and Vilmundur Gudnason and Orwoll, {Eric S} and Harris, {Tamara B} and Claes Ohlsson and Kiel, {Douglas P} and Yi-Hsiang Hsu",

year = "2016",

month = dec,

doi = "10.1002/jbmr.2913",

language = "English",

volume = "31",

journal = "Journal of Bone and Mineral Research",

issn = "0884-0431",

publisher = "Wiley-Blackwell",

number = "12",

}

Nielson, CM, Liu, C-T, Smith, AV, Ackert-Bicknell, CL, Reppe, S, Johanna, J, Wassel, C, Register, TC, Oei, L, Alonso Lopez, N, Oei, EH, Parimi, N, Samelson, EJ, Nalls, MA, Zmuda, J, Lang, T, Bouxsein, M, Latourelle, J, Claussnitzer, M, Siggeirsdottir, K, Srikanth, P, Lorentzen, E, Vandenput, L, Langefeld, C, Raffield, L, Terry, G, Cox, AJ, Allison, MA, Criqui, MH, Bowden, D, Ikram, MA, Mellström, D, Karlsson, MK, Carr, J, Budoff, M, Phillips, C, Cupples, LA, Chou, W-C, Myers, RH, Ralston, SH, Gautvik, KM, Cawthon, PM, Cummings, S, Karasik, D, Rivadeneira, F, Gudnason, V, Orwoll, ES, Harris, TB, Ohlsson, C, Kiel, DP & Hsu, Y-H 2016, 'Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2', Journal of Bone and Mineral Research, vol. 31, no. 12. https://doi.org/10.1002/jbmr.2913

TY - JOUR

T1 - Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2

AU - Nielson, Carrie M

AU - Liu, Ching-Ti

AU - Smith, Albert V

AU - Ackert-Bicknell, Cheryl L

AU - Reppe, Sjur

AU - Johanna, Jakobsdottir

AU - Wassel, Christina

AU - Register, Thomas C

AU - Oei, Ling

AU - Alonso Lopez, Nerea

AU - Oei, Edwin H

AU - Parimi, Neeta

AU - Samelson, Elizabeth J

AU - Nalls, Mike A

AU - Zmuda, Joseph

AU - Lang, Thomas

AU - Bouxsein, Mary

AU - Latourelle, Jeanne

AU - Claussnitzer, Melina

AU - Siggeirsdottir, Kristin

AU - Srikanth, Priya

AU - Lorentzen, Erik

AU - Vandenput, Liesbeth

AU - Langefeld, Carl

AU - Raffield, Laura

AU - Terry, Greg

AU - Cox, Amanda J

AU - Allison, Matthew A

AU - Criqui, Michael H

AU - Bowden, Don

AU - Ikram, M Arfan

AU - Mellström, Dan

AU - Karlsson, Magnus K

AU - Carr, John

AU - Budoff, Matthew

AU - Phillips, Caroline

AU - Cupples, L Adrienne

AU - Chou, Wen-Chi

AU - Myers, Richard H

AU - Ralston, Stuart H

AU - Gautvik, Kaare M

AU - Cawthon, Peggy M

AU - Cummings, Steven

AU - Karasik, David

AU - Rivadeneira, Fernando

AU - Gudnason, Vilmundur

AU - Orwoll, Eric S

AU - Harris, Tamara B

AU - Ohlsson, Claes

AU - Kiel, Douglas P

AU - Hsu, Yi-Hsiang

PY - 2016/12

Y1 - 2016/12

N2 - Genome-wide association studies (GWAS) 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 in (N = 21,701) and clinical vertebral fracture (N = 5,893). Expression QTL 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 (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 non-coding 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. This article is protected by copyright. All rights reserved.

AB - Genome-wide association studies (GWAS) 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 in (N = 21,701) and clinical vertebral fracture (N = 5,893). Expression QTL 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 (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 non-coding 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. This article is protected by copyright. All rights reserved.

U2 - 10.1002/jbmr.2913

DO - 10.1002/jbmr.2913

M3 - Article

C2 - 27476799

VL - 31

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 12

ER -

Novel Genetic Variants are Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SCL1A3 and EPHB2

Abstract

Access to Document

Fingerprint

Cite this