Format

Send to:

Choose Destination
See comment in PubMed Commons below
PLoS Genet. 2014 Jun 19;10(6):e1004423. doi: 10.1371/journal.pgen.1004423. eCollection 2014.

Phenotypic dissection of bone mineral density reveals skeletal site specificity and facilitates the identification of novel loci in the genetic regulation of bone mass attainment.

Author information

  • 1MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
  • 2Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands.
  • 3Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
  • 4MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; School of Oral and Dental Sciences, University of Bristol, Bristol, United Kingdom; School of Experimental Psychology, University of Bristol, Bristol, United Kingdom.
  • 5The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Paediatrics, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 6University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
  • 7Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands.
  • 8MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
  • 9The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 10Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
  • 11Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway.
  • 12Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway; Department of Medical Biochemistry, Oslo Deacon Hospital, Oslo, Norway.
  • 13Department of Human Genetics, McGill University, Montréal, Canada; McGill University and Genome Québec Innovation Centre, Montréal, Canada.
  • 14McGill University and Genome Québec Innovation Centre, Montréal, Canada.
  • 15Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • 16Department of Computer Science, Trinity University, San Antonio, Texas, United States of America; The Jackson Laboratory, Bar Harbor, Maine, United States of America.
  • 17The Jackson Laboratory, Bar Harbor, Maine, United States of America.
  • 18Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
  • 19Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
  • 20Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands.
  • 21Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
  • 22The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands.
  • 23School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.

Abstract

Heritability of bone mineral density (BMD) varies across skeletal sites, reflecting different relative contributions of genetic and environmental influences. To quantify the degree to which common genetic variants tag and environmental factors influence BMD, at different sites, we estimated the genetic (rg) and residual (re) correlations between BMD measured at the upper limbs (UL-BMD), lower limbs (LL-BMD) and skull (SK-BMD), using total-body DXA scans of ∼ 4,890 participants recruited by the Avon Longitudinal Study of Parents and their Children (ALSPAC). Point estimates of rg indicated that appendicular sites have a greater proportion of shared genetic architecture (LL-/UL-BMD rg = 0.78) between them, than with the skull (UL-/SK-BMD rg = 0.58 and LL-/SK-BMD rg = 0.43). Likewise, the residual correlation between BMD at appendicular sites (r(e) = 0.55) was higher than the residual correlation between SK-BMD and BMD at appendicular sites (r(e) = 0.20-0.24). To explore the basis for the observed differences in rg and re, genome-wide association meta-analyses were performed (n ∼ 9,395), combining data from ALSPAC and the Generation R Study identifying 15 independent signals from 13 loci associated at genome-wide significant level across different skeletal regions. Results suggested that previously identified BMD-associated variants may exert site-specific effects (i.e. differ in the strength of their association and magnitude of effect across different skeletal sites). In particular, variants at CPED1 exerted a larger influence on SK-BMD and UL-BMD when compared to LL-BMD (P = 2.01 × 10(-37)), whilst variants at WNT16 influenced UL-BMD to a greater degree when compared to SK- and LL-BMD (P = 2.31 × 10(-14)). In addition, we report a novel association between RIN3 (previously associated with Paget's disease) and LL-BMD (rs754388: β = 0.13, SE = 0.02, P = 1.4 × 10(-10)). Our results suggest that BMD at different skeletal sites is under a mixture of shared and specific genetic and environmental influences. Allowing for these differences by performing genome-wide association at different skeletal sites may help uncover new genetic influences on BMD.

PMID:
24945404
[PubMed - indexed for MEDLINE]
PMCID:
PMC4063697
Free PMC Article

Publication Types, MeSH Terms, Substances, Secondary Source ID, Grant Support

Publication Types

MeSH Terms

Substances

Secondary Source ID

Grant Support

PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Write to the Help Desk