Osteoporosis International

, Volume 21, Issue 4, pp 579–587

Genome-wide copy number variation association study suggested VPS13B gene for osteoporosis in Caucasians

  • F.-Y. Deng
  • L.-J. Zhao
  • Y.-F. Pei
  • B.-Y. Sha
  • X.-G. Liu
  • H. Yan
  • L. Wang
  • T.-L. Yang
  • R. R. Recker
  • C. J. Papasian
  • H.-W. Deng
Original Article

DOI: 10.1007/s00198-009-0998-7

Cite this article as:
Deng, FY., Zhao, LJ., Pei, YF. et al. Osteoporos Int (2010) 21: 579. doi:10.1007/s00198-009-0998-7

Abstract

Summary

Osteoporotic fracture (OF) is a serious outcome of osteoporosis. Important risk factors for OF include reduced bone mineral density and unstable bone structure. This genome-wide copy number variation association study suggested VPS13B gene for osteoporosis in Caucasians.

Introduction

Bone mineral density (BMD) and femoral neck cross-sectional geometric parameters (FNCSGPs) are under strong genetic control. DNA copy number variation (CNV) is an important source of genetic diversity for human diseases. This study aims to identify CNVs associated with BMD and FNCSGPs.

Methods

Genome-wide CNV association analyses were conducted in 1,000 unrelated Caucasian subjects for BMD at the spine, hip, femoral neck, and for three FNCSGPs —cortical thickness (CT), cross-section area (CSA), and buckling ratio (BR). BMD was measured by dual energy X-ray absorptiometry (DEXA). CT, CSA, and BR were estimated using DEXA measurements. Affymetrix 500K arrays and copy number analysis tool was used to identify CNVs.

Results

A CNV in VPS13B gene was significantly associated with spine, hip and FN BMDs, and CT, CSA, and BR (p < 0.05). Compared to subjects with two copies of the CNV, carriers of one copy had an average of 14.6%, 12.4%, and 13.6% higher spine, hip, and FN BMD, 20.0% thicker CT, 10.6% larger CSA, and 12.4% lower BR. Thus, a decrease of the CNV consistently produced stronger bone, thereby reducing osteoporotic fracture risk.

Conclusions

VPS13B gene, via affecting BMD and FNCSGPs, is a novel osteoporosis risk gene.

Keywords

Bone geometryBone mineral densityCopy number variationOsteoporosis

Supplementary material

198_2009_998_MOESM1_ESM.doc (48 kb)
Supplement 1Illustration of the relationship among SNPs, CNVs, CNVRs, and CNV subregions. Briefly, CNVs detected are marked and bounded by Affymetrix 500K SNPs, and they vary not only in copy numbers but also in length, so the variant unit’s sequence coverage may differ between subjects. Along a specific chromosome, the length of each variant unit in a certain subject was determined by the corresponding sequentially located SNPs’ signal intensity changes against reference signals; a longer or shorter variant unit (involving more or less SNPs for different subjects) could be recognized and called (reported) by software CNAT; calls 1, 2, 3, 4 represent variant units for four random subjects. CNVRs represent genomic regions covering overlapping CNVs; in this study, complex CNVRs, which contains CNVs with inconsistent boundaries, were divided into several CNV subregions. Subregions defined thereby have the same conservative boundary among subjects. (DOC 47 kb)
198_2009_998_MOESM2_ESM.xls (152 kb)
Supplement 2Information of 243 CNV subregions. A total of 243 CNV IDs were assigned. Since the exact boundaries of CNVs cannot be obtained from data produced by the Affymetrix 500K SNP genotyping platform, they are approximated by physical positions (NCBI Build 36.1, March 2006) of the probe pairs having the maximal distance within a CNV, yielding conservatively shorter defined sizes of CNVs than the actual sizes. In the sheet “CNV Subregions”, the Start and End Physical Position is for the approximate boundary probe pairs. A length of “–” means that the CNV subregion was assigned by only one Probe Set; thus, the length was undefined. “Number with CNV Loss”, “Number with Normal CNV”, and “Number with CNV Gain” are the number of individuals carrying the specific CN state among the 985 Caucasian subjects. “CNV Frequency” is the percentage of subjects who do not have a normal CNV among the Caucasian sample. “Associated Gene” shows genes overlapped with the CNV. In the sheet “Probe Sets”, we list the sequential probe sets on Affymetrix 500K SNPs arrays within the corresponding CNVs. (XLS 152 kb)
198_2009_998_MOESM3_ESM.xls (39 kb)
Supplement 3CNV associations with BMD and FNCSGPs. All nominal significant associations (p < 0.05) between CNV and BMD or FNCSGPs across the whole genome are presented. p values less than 0.01 are italicized. (XLS 39 kb)

Copyright information

© International Osteoporosis Foundation and National Osteoporosis Foundation 2009

Authors and Affiliations

  • F.-Y. Deng
    • 1
  • L.-J. Zhao
    • 2
  • Y.-F. Pei
    • 1
    • 3
  • B.-Y. Sha
    • 4
  • X.-G. Liu
    • 3
  • H. Yan
    • 3
  • L. Wang
    • 3
  • T.-L. Yang
    • 1
  • R. R. Recker
    • 2
  • C. J. Papasian
    • 1
  • H.-W. Deng
    • 1
    • 3
    • 4
  1. 1.School of MedicineUniversity of Missouri—Kansas CityKansas CityUSA
  2. 2.Osteoporosis Research CenterCreighton UniversityOmahaUSA
  3. 3.The Key Laboratory of Biomedical Information Engineering of Ministry of Education and Institute of Molecular Genetics, School of Life Science and TechnologyXi’an Jiaotong UniversityXi’an, ShannxiPeople’s Republic of China
  4. 4.Laboratory of Molecular and Statistical Genetics, College of Life SciencesHunan Normal UniversityHunanPeople’s Republic of China