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

Carrie 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 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 Orwoll, Tamara B. Harris, Claes Ohlsson, Douglas P. Kiel, Yi Hsiang Hsu

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2085-2097
Number of pages13
JournalJournal of Bone and Mineral Research
Volume31
Issue number12
DOIs
StatePublished - Dec 1 2016

Fingerprint

Genome-Wide Association Study
Single Nucleotide Polymorphism
Quantitative Trait Loci
Osteoblasts
Gene Frequency
Bone and Bones
Meta-Analysis
Odds Ratio
Ephrins
Biopsy
Bone Density
Osteoporosis
Glutamic Acid
Spine
Tomography
Phenotype
Gene Expression
Messenger RNA
Incidence
Genes

Keywords

  • 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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2. / Nielson, Carrie; 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; 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; Harris, Tamara B.; Ohlsson, Claes; Kiel, Douglas P.; Hsu, Yi Hsiang.

In: Journal of Bone and Mineral Research, Vol. 31, No. 12, 01.12.2016, p. 2085-2097.

Research output: Contribution to journalArticle

Nielson, C, Liu, CT, Smith, AV, Ackert-Bicknell, CL, Reppe, S, Jakobsdottir, J, Wassel, C, Register, TC, Oei, L, Alonso, 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, WC, Myers, RH, Ralston, SH, Gautvik, KM, Cawthon, PM, Cummings, S, Karasik, D, Rivadeneira, F, Gudnason, V, Orwoll, E, Harris, TB, Ohlsson, C, Kiel, DP & Hsu, YH 2016, 'Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2', Journal of Bone and Mineral Research, vol. 31, no. 12, pp. 2085-2097. https://doi.org/10.1002/jbmr.2913
Nielson, Carrie ; 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 ; 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 ; Harris, Tamara B. ; Ohlsson, Claes ; Kiel, Douglas P. ; Hsu, Yi Hsiang. / Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2. In: Journal of Bone and Mineral Research. 2016 ; Vol. 31, No. 12. pp. 2085-2097.
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title = "Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2",
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.",
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author = "Carrie Nielson and Liu, {Ching Ti} and Smith, {Albert V.} and Ackert-Bicknell, {Cheryl L.} and Sjur Reppe and Johanna Jakobsdottir and Christina Wassel and Register, {Thomas C.} and Ling Oei and Nerea Alonso 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 Chou, {Wen Chi} 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 Eric Orwoll and Harris, {Tamara B.} and Claes Ohlsson and Kiel, {Douglas P.} and Hsu, {Yi Hsiang}",
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TY - JOUR

T1 - Novel Genetic Variants Associated With Increased Vertebral Volumetric BMD, Reduced Vertebral Fracture Risk, and Increased Expression of SLC1A3 and EPHB2

AU - Nielson, Carrie

AU - Liu, Ching Ti

AU - Smith, Albert V.

AU - Ackert-Bicknell, Cheryl L.

AU - Reppe, Sjur

AU - Jakobsdottir, Johanna

AU - Wassel, Christina

AU - Register, Thomas C.

AU - Oei, Ling

AU - Alonso, 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

AU - Harris, Tamara B.

AU - Ohlsson, Claes

AU - Kiel, Douglas P.

AU - Hsu, Yi Hsiang

PY - 2016/12/1

Y1 - 2016/12/1

N2 - 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.

AB - 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.

KW - ANALYSIS/QUANTITATION OF BONE

KW - BONE QCT/μCT

KW - DISEASES AND DISORDERS OF/RELATED TO BONE

KW - EPIDEMIOLOGY, HUMAN ASSOCIATION STUDIES

KW - FRACTURE RISK ASSESSMENT

KW - GENERAL POPULATION STUDIES

KW - GENETIC RESEARCH

KW - OSTEOPOROSIS

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DO - 10.1002/jbmr.2913

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VL - 31

SP - 2085

EP - 2097

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

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