title: 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.
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.
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.affiliation: 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.
authors.forename: Carolina
authors.initials: C
authors.lastname: Medina-Gomez
authors.affiliation: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.affiliation: 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.
authors.forename: Beate
authors.initials: B
authors.lastname: St Pourcain
authors.affiliation: 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.
authors.forename: Denise H M
authors.initials: DH
authors.lastname: Heppe
authors.affiliation: University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Warrington
authors.affiliation: 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Oei
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ring
authors.affiliation: The Generation R Study Group, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Claudia J
authors.initials: CJ
authors.lastname: Kruithof
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Lisa E
authors.initials: LE
authors.lastname: Wolber
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway.
authors.forename: Sjur
authors.initials: S
authors.lastname: Reppe
authors.affiliation: Department of Medical Biochemistry, Oslo University Hospital, Ullevaal, Oslo, Norway; Department of Medical Biochemistry, Oslo Deacon Hospital, Oslo, Norway.
authors.forename: Kaare
authors.initials: K
authors.lastname: Gautvik
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Canada; McGill University and Genome Québec Innovation Centre, Montréal, Canada.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.affiliation: McGill University and Genome Québec Innovation Centre, Montréal, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Bram
authors.initials: B
authors.lastname: van der Eerden
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van de Peppel
authors.affiliation: Department of Computer Science, Trinity University, San Antonio, Texas, United States of America; The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hibbs
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Ackert-Bicknell
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, United States of America.
authors.forename: Kwangbom
authors.initials: K
authors.lastname: Choi
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Koller
authors.affiliation: 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.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Econs
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
authors.forename: Frances M K
authors.initials: FM
authors.lastname: Williams
authors.affiliation: Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), The Netherlands.
authors.forename: M Carola
authors.initials: MC
authors.lastname: Zillikens
authors.affiliation: Center for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: 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.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: 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.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom.
authors.forename: George
authors.initials: G
authors.lastname: Davey Smith
authors.affiliation: 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.
authors.forename: Vincent W V
authors.initials: VW
authors.lastname: Jaddoe
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Tobias
authors.affiliation: 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.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, United Kingdom; University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
mesh_terms: D000328:Adult; D015519:Bone Density / Q000235:genetics*; D001846:Bone Development; D001842:Bone and Bones / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D005260:Female; D055106:Genome-Wide Association Study; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D008137:Longitudinal Studies; D035002:Lower Extremity / Q000254:growth & development / Q000502:physiology; D008297:Male; D010024:Osteoporosis / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D011446:Prospective Studies; D012886:Skull / Q000254:growth & development / Q000502:physiology; D034941:Upper Extremity / Q000254:growth & development / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D020662:Guanine Nucleotide Exchange Factors; C487967:RIN3 protein, human; C417262:WNT16 protein, human; D051153:Wnt Proteins