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

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

doi:10.1002/jbmr.2913

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

J Bone Miner Res. 2016 Dec;31(12):2085-2097. doi: 10.1002/jbmr.2913. Epub 2016 Sep 6.

Authors

Carrie M Nielson¹, Ching-Ti Liu², Albert V Smith^{3

4}, Cheryl L Ackert-Bicknell⁵, Sjur Reppe^{6

7

8}, Johanna Jakobsdottir³, Christina Wassel⁹, Thomas C Register¹⁰, Ling Oei^{11

12}, Nerea Alonso¹³, Edwin H Oei¹⁴, Neeta Parimi¹⁵, Elizabeth J Samelson¹⁶, Mike A Nalls¹⁷, Joseph Zmuda¹⁸, Thomas Lang¹⁹, Mary Bouxsein²⁰, Jeanne Latourelle²¹, Melina Claussnitzer^{22

23

24}, Kristin Siggeirsdottir²⁵, Priya Srikanth¹, Erik Lorentzen²⁶, Liesbeth Vandenput²⁷, Carl Langefeld²⁸, Laura Raffield^{29

30}, Greg Terry³¹, Amanda J Cox³², Matthew A Allison³³, Michael H Criqui³³, Don Bowden^{32

34

35}, M Arfan Ikram³⁶, Dan Mellström²⁷, Magnus K Karlsson³⁷, John Carr³¹, Matthew Budoff³⁸, Caroline Phillips¹⁷, L Adrienne Cupples², Wen-Chi Chou²³, Richard H Myers²¹, Stuart H Ralston³⁹, Kaare M Gautvik^{7

8}, Peggy M Cawthon^{15

40}, Steven Cummings¹⁵, David Karasik^{16

41}, Fernando Rivadeneira^{36

42}, Vilmundur Gudnason^{3

4}, Eric S Orwoll⁴³, Tamara B Harris¹⁷, Claes Ohlsson²⁷, Douglas P Kiel^{16

22}, Yi-Hsiang Hsu^{16

23

44}

Affiliations

¹ School of Public Health, Oregon Health & Science University, Portland, OR, USA.
² Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA.
³ Icelandic Heart Association, Kópavogur, Iceland.
⁴ Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
⁵ Department of Orthopaedics and Rehabilitation, University of Rochester, Rochester, NY, USA.
⁶ Department of Medical Biochemistry, Oslo University Hospital, Ullevål, Oslo, Norway.
⁷ Lovisenberg Diakonale Hospital, Oslo, Norway.
⁸ Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway.
⁹ Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Burlington, VT, USA.
¹⁰ Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
¹¹ Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹² Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands.
¹³ Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK.
¹⁴ Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, The Netherlands.
¹⁵ California Pacific Medical Center Research Institute, San Francisco, CA, USA.
¹⁶ Institute for Aging Research, Hebrew SeniorLife, Harvard Medical School, Boston, MA, USA.
¹⁷ National Institute on Aging (NIA), National Institutes of Health, Bethesda, MD, USA.
¹⁸ Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, USA.
¹⁹ Department of Radiology, University of California, San Francisco (UCSF) School of Medicine, San Francisco, CA, USA.
²⁰ Center for Advanced Orthopedic Studies, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA.
²¹ Department of Neurology, Boston University, Boston, MA, USA.
²² Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA, USA.
²³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁴ Technical University Munich, Munich, Germany.
²⁵ Imaging, Icelandic Heart Association, Kópavogur, Iceland.
²⁶ Department of Bioinformatics, Gothenburg University, Gothenburg, Sweden.
²⁷ Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
²⁸ Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
²⁹ Center for Human Genomics, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁰ Center for Diabetes Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³¹ Department of Radiology & Radiological Sciences, Vanderbilt University Medical Center, Vanderbilt University, Nashville, TN, USA.
³² Center for Diabetes Research, Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³³ Department of Family Medicine and Public Health, University of California, San Diego (UCSD), La Jolla, CA, USA.
³⁴ Internal Medicine/Endocrinology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁵ Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston-Salem, NC, USA.
³⁶ Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.
³⁷ Department of Orthopaedics and Clinical Sciences, Malmö University Hospital, Lund University, Malmö, Sweden.
³⁸ Los Angeles Biomedical Research Institute, Torrance, CA, USA.
³⁹ Rheumatic Diseases Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland, UK.
⁴⁰ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
⁴¹ Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel.
⁴² Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
⁴³ Division of Endocrinology, Oregon Health & Science University, Portland, OR, USA.
⁴⁴ Molecular and Integrative Physiological Sciences, Harvard School of Public Health, Boston, MA, USA.

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: 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Biopsy
Bone Density / genetics*
Cancellous Bone / diagnostic imaging
Cancellous Bone / pathology
Cancellous Bone / physiopathology
Excitatory Amino Acid Transporter 1 / genetics*
Excitatory Amino Acid Transporter 1 / metabolism
Gene Expression Regulation
Genetic Association Studies*
Genetic Predisposition to Disease*
Humans
Linkage Disequilibrium / genetics
Lumbar Vertebrae / diagnostic imaging
Lumbar Vertebrae / pathology
Lumbar Vertebrae / physiopathology
Mice
Molecular Sequence Annotation
Organ Size
Osteoblasts / metabolism
Polymorphism, Single Nucleotide / genetics*
Quantitative Trait Loci / genetics
Receptor, EphB2 / genetics*
Receptor, EphB2 / metabolism
Risk Factors
Spinal Fractures / diagnostic imaging
Spinal Fractures / genetics*
Spinal Fractures / pathology
Spinal Fractures / physiopathology
Spine / diagnostic imaging
Spine / pathology*

Substances

Excitatory Amino Acid Transporter 1
SLC1A3 protein, human
EPHB2 protein, human
Receptor, EphB2

Abstract

Publication types

MeSH terms

Substances

Grants and funding