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.

Autor:	Kemp JP; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia., Medina-Gomez C; Department 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., Estrada K; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America., St Pourcain B; MRC 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., Heppe DH; The 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., Warrington NM; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia., Oei L; Department 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., Ring SM; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom., Kruithof CJ; The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands., Timpson NJ; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom., Wolber LE; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom., Reppe S; Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway., Gautvik K; Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway; Department of Medical Biochemistry, Oslo Deacon Hospital, Oslo, Norway., Grundberg E; Department of Human Genetics, McGill University, Montréal, Canada; McGill University and Genome Québec Innovation Centre, Montréal, Canada., Ge B; McGill University and Genome Québec Innovation Centre, Montréal, Canada., van der Eerden B; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands., van de Peppel J; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands., Hibbs MA; Department of Computer Science, Trinity University, San Antonio, Texas, United States of America; The Jackson Laboratory, Bar Harbor, Maine, United States of America., Ackert-Bicknell CL; The Jackson Laboratory, Bar Harbor, Maine, United States of America., Choi K; The Jackson Laboratory, Bar Harbor, Maine, United States of America., Koller DL; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America., Econs MJ; Department 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., Williams FM; Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom., Foroud T; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America., Zillikens MC; Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands., Ohlsson C; Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden., Hofman A; 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., Uitterlinden AG; Department 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., Davey Smith G; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom., Jaddoe VW; The 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., Tobias JH; School of Clinical Sciences, University of Bristol, Bristol, United Kingdom., Rivadeneira F; Department 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., Evans DM; MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
Jazyk:	angličtina
Zdroj:	PLoS genetics [PLoS Genet] 2014 Jun 19; Vol. 10 (6), pp. e1004423. Date of Electronic Publication: 2014 Jun 19 (Print Publication: 2014).
DOI:	10.1371/journal.pgen.1004423
Abstrakt:	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.
Databáze:	MEDLINE
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