Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk
Identifieur interne : 002874 ( Pmc/Corpus ); précédent : 002873; suivant : 002875Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk
Auteurs : Emma L. Duncan ; Patrick Danoy ; John P. Kemp ; Paul J. Leo ; Eugene Mccloskey ; Geoffrey C. Nicholson ; Richard Eastell ; Richard L. Prince ; John A. Eisman ; Graeme Jones ; Philip N. Sambrook ; Ian R. Reid ; Elaine M. Dennison ; John Wark ; J. Brent Richards ; Andre G. Uitterlinden ; Tim D. Spector ; Chris Esapa ; Roger D. Cox ; Steve D. M. Brown ; Rajesh V. Thakker ; Kathryn A. Addison ; Linda A. Bradbury ; Jacqueline R. Center ; Cyrus Cooper ; Catherine Cremin ; Karol Estrada ; Dieter Felsenberg ; Claus-C. Glüer ; Johanna Hadler ; Margaret J. Henry ; Albert Hofman ; Mark A. Kotowicz ; Joanna Makovey ; Sing C. Nguyen ; Tuan V. Nguyen ; Julie A. Pasco ; Karena Pryce ; David M. Reid ; Fernando Rivadeneira ; Christian Roux ; Kari Stefansson ; Unnur Styrkarsdottir ; Gudmar Thorleifsson ; Rumbidzai Tichawangana ; David M. Evans ; Matthew A. BrownSource :
- PLoS Genetics [ 1553-7390 ] ; 2011.
Abstract
Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low
bone mineral density (BMD) is a major predisposing factor to fracture and is
known to be highly heritable. Site-, gender-, and age-specific genetic effects
on BMD are thought to be significant, but have largely not been considered in
the design of genome-wide association studies (GWAS) of BMD to date. We report
here a GWAS using a novel study design focusing on women of a specific age
(postmenopausal women, age 55–85 years), with either extreme high or low
hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0,
n = 1055, or −4.0 to −1.5,
n = 900), with replication in cohorts of women drawn from
the general population (n = 20,898). The study replicates
21 of 26 known BMD–associated genes. Additionally, we report suggestive
association of a further six new genetic associations in or around the genes
Url:
DOI: 10.1371/journal.pgen.1001372
PubMed: 21533022
PubMed Central: 3080863
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PMC:3080863Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Genome-Wide Association Study Using Extreme Truncate Selection
Identifies Novel Genes Affecting Bone Mineral Density and Fracture
Risk</title><author><name sortKey="Duncan, Emma L" sort="Duncan, Emma L" uniqKey="Duncan E" first="Emma L." last="Duncan">Emma L. Duncan</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Danoy, Patrick" sort="Danoy, Patrick" uniqKey="Danoy P" first="Patrick" last="Danoy">Patrick Danoy</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kemp, John P" sort="Kemp, John P" uniqKey="Kemp J" first="John P." last="Kemp">John P. Kemp</name><affiliation><nlm:aff id="aff2"><addr-line>Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Leo, Paul J" sort="Leo, Paul J" uniqKey="Leo P" first="Paul J." last="Leo">Paul J. Leo</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mccloskey, Eugene" sort="Mccloskey, Eugene" uniqKey="Mccloskey E" first="Eugene" last="Mccloskey">Eugene Mccloskey</name><affiliation><nlm:aff id="aff3"><addr-line>Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nicholson, Geoffrey C" sort="Nicholson, Geoffrey C" uniqKey="Nicholson G" first="Geoffrey C." last="Nicholson">Geoffrey C. Nicholson</name><affiliation><nlm:aff id="aff4"><addr-line>The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eastell, Richard" sort="Eastell, Richard" uniqKey="Eastell R" first="Richard" last="Eastell">Richard Eastell</name><affiliation><nlm:aff id="aff3"><addr-line>Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Prince, Richard L" sort="Prince, Richard L" uniqKey="Prince R" first="Richard L." last="Prince">Richard L. Prince</name><affiliation><nlm:aff id="aff5"><addr-line>School of Medicine and Pharmacology, University of Western Australia, Perth, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eisman, John A" sort="Eisman, John A" uniqKey="Eisman J" first="John A." last="Eisman">John A. Eisman</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>St. Vincent's Clinical School, St. Vincent's Hospital Campus, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jones, Graeme" sort="Jones, Graeme" uniqKey="Jones G" first="Graeme" last="Jones">Graeme Jones</name><affiliation><nlm:aff id="aff9"><addr-line>Menzies Research Institute, University of Tasmania, Hobart, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sambrook, Philip N" sort="Sambrook, Philip N" uniqKey="Sambrook P" first="Philip N." last="Sambrook">Philip N. Sambrook</name><affiliation><nlm:aff id="aff10"><addr-line>Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reid, Ian R" sort="Reid, Ian R" uniqKey="Reid I" first="Ian R." last="Reid">Ian R. Reid</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Medicine, University of Auckland, Auckland, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dennison, Elaine M" sort="Dennison, Elaine M" uniqKey="Dennison E" first="Elaine M." last="Dennison">Elaine M. Dennison</name><affiliation><nlm:aff id="aff12"><addr-line>Medical Research Council Lifecourse Epidemiology Unit, Southampton, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wark, John" sort="Wark, John" uniqKey="Wark J" first="John" last="Wark">John Wark</name><affiliation><nlm:aff id="aff13"><addr-line>University of Melbourne Department of Medicine and Bone and Mineral Service, Royal Melbourne Hospital, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Richards, J Brent" sort="Richards, J Brent" uniqKey="Richards J" first="J. Brent" last="Richards">J. Brent Richards</name><affiliation><nlm:aff id="aff14"><addr-line>Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><addr-line>Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="Andre G." last="Uitterlinden">Andre G. Uitterlinden</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Spector, Tim D" sort="Spector, Tim D" uniqKey="Spector T" first="Tim D." last="Spector">Tim D. Spector</name><affiliation><nlm:aff id="aff15"><addr-line>Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Esapa, Chris" sort="Esapa, Chris" uniqKey="Esapa C" first="Chris" last="Esapa">Chris Esapa</name><affiliation><nlm:aff id="aff17"><addr-line>Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, Oxfordshire, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><addr-line>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Roger D" sort="Cox, Roger D" uniqKey="Cox R" first="Roger D." last="Cox">Roger D. Cox</name><affiliation><nlm:aff id="aff17"><addr-line>Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, Oxfordshire, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brown, Steve D M" sort="Brown, Steve D M" uniqKey="Brown S" first="Steve D. M." last="Brown">Steve D. M. Brown</name><affiliation><nlm:aff id="aff17"><addr-line>Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, Oxfordshire, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Thakker, Rajesh V" sort="Thakker, Rajesh V" uniqKey="Thakker R" first="Rajesh V." last="Thakker">Rajesh V. Thakker</name><affiliation><nlm:aff id="aff18"><addr-line>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Addison, Kathryn A" sort="Addison, Kathryn A" uniqKey="Addison K" first="Kathryn A." last="Addison">Kathryn A. Addison</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bradbury, Linda A" sort="Bradbury, Linda A" uniqKey="Bradbury L" first="Linda A." last="Bradbury">Linda A. Bradbury</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Center, Jacqueline R" sort="Center, Jacqueline R" uniqKey="Center J" first="Jacqueline R." last="Center">Jacqueline R. Center</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>St. Vincent's Clinical School, St. Vincent's Hospital Campus, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cooper, Cyrus" sort="Cooper, Cyrus" uniqKey="Cooper C" first="Cyrus" last="Cooper">Cyrus Cooper</name><affiliation><nlm:aff id="aff12"><addr-line>Medical Research Council Lifecourse Epidemiology Unit, Southampton, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>National Institute for Health and Research Biomedical Research Unit, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cremin, Catherine" sort="Cremin, Catherine" uniqKey="Cremin C" first="Catherine" last="Cremin">Catherine Cremin</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Estrada, Karol" sort="Estrada, Karol" uniqKey="Estrada K" first="Karol" last="Estrada">Karol Estrada</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Felsenberg, Dieter" sort="Felsenberg, Dieter" uniqKey="Felsenberg D" first="Dieter" last="Felsenberg">Dieter Felsenberg</name><affiliation><nlm:aff id="aff20"><addr-line>Centre of Muscle and Bone Research, Charité – University Medicine Berlin, Campus Benjamin Franklin, Free and Humboldt University, Berlin, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gluer, Claus C" sort="Gluer, Claus C" uniqKey="Gluer C" first="Claus-C." last="Glüer">Claus-C. Glüer</name><affiliation><nlm:aff id="aff21"><addr-line>Medizinische Physik, Klinik für Diagnostische Radiologie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hadler, Johanna" sort="Hadler, Johanna" uniqKey="Hadler J" first="Johanna" last="Hadler">Johanna Hadler</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Henry, Margaret J" sort="Henry, Margaret J" uniqKey="Henry M" first="Margaret J." last="Henry">Margaret J. Henry</name><affiliation><nlm:aff id="aff22"><addr-line>School of Medicine, Deakin University, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kotowicz, Mark A" sort="Kotowicz, Mark A" uniqKey="Kotowicz M" first="Mark A." last="Kotowicz">Mark A. Kotowicz</name><affiliation><nlm:aff id="aff23"><addr-line>Department of Endocrinology and Diabetes, Barwon Health, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Makovey, Joanna" sort="Makovey, Joanna" uniqKey="Makovey J" first="Joanna" last="Makovey">Joanna Makovey</name><affiliation><nlm:aff id="aff24"><addr-line>Institute of Bone Joint Research, University of Sydney, Royal North Shore Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nguyen, Sing C" sort="Nguyen, Sing C" uniqKey="Nguyen S" first="Sing C." last="Nguyen">Sing C. Nguyen</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nguyen, Tuan V" sort="Nguyen, Tuan V" uniqKey="Nguyen T" first="Tuan V." last="Nguyen">Tuan V. Nguyen</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>St. Vincent's Clinical School, St. Vincent's Hospital Campus, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pasco, Julie A" sort="Pasco, Julie A" uniqKey="Pasco J" first="Julie A." last="Pasco">Julie A. Pasco</name><affiliation><nlm:aff id="aff22"><addr-line>School of Medicine, Deakin University, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pryce, Karena" sort="Pryce, Karena" uniqKey="Pryce K" first="Karena" last="Pryce">Karena Pryce</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reid, David M" sort="Reid, David M" uniqKey="Reid D" first="David M." last="Reid">David M. Reid</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rivadeneira, Fernando" sort="Rivadeneira, Fernando" uniqKey="Rivadeneira F" first="Fernando" last="Rivadeneira">Fernando Rivadeneira</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Roux, Christian" sort="Roux, Christian" uniqKey="Roux C" first="Christian" last="Roux">Christian Roux</name><affiliation><nlm:aff id="aff27"><addr-line>Rheumatology Department, AP-HP Cochin Hospital – Paris-Descartes University, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stefansson, Kari" sort="Stefansson, Kari" uniqKey="Stefansson K" first="Kari" last="Stefansson">Kari Stefansson</name><affiliation><nlm:aff id="aff28"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff29"><addr-line>University of Iceland, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Styrkarsdottir, Unnur" sort="Styrkarsdottir, Unnur" uniqKey="Styrkarsdottir U" first="Unnur" last="Styrkarsdottir">Unnur Styrkarsdottir</name><affiliation><nlm:aff id="aff28"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Thorleifsson, Gudmar" sort="Thorleifsson, Gudmar" uniqKey="Thorleifsson G" first="Gudmar" last="Thorleifsson">Gudmar Thorleifsson</name><affiliation><nlm:aff id="aff28"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tichawangana, Rumbidzai" sort="Tichawangana, Rumbidzai" uniqKey="Tichawangana R" first="Rumbidzai" last="Tichawangana">Rumbidzai Tichawangana</name><affiliation><nlm:aff id="aff4"><addr-line>The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Evans, David M" sort="Evans, David M" uniqKey="Evans D" first="David M." last="Evans">David M. Evans</name><affiliation><nlm:aff id="aff2"><addr-line>Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brown, Matthew A" sort="Brown, Matthew A" uniqKey="Brown M" first="Matthew A." last="Brown">Matthew A. Brown</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>National Institute for Health and Research Biomedical Research Unit, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21533022</idno><idno type="pmc">3080863</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080863</idno><idno type="RBID">PMC:3080863</idno><idno type="doi">10.1371/journal.pgen.1001372</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">002874</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">002874</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Genome-Wide Association Study Using Extreme Truncate Selection
Identifies Novel Genes Affecting Bone Mineral Density and Fracture
Risk</title><author><name sortKey="Duncan, Emma L" sort="Duncan, Emma L" uniqKey="Duncan E" first="Emma L." last="Duncan">Emma L. Duncan</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Danoy, Patrick" sort="Danoy, Patrick" uniqKey="Danoy P" first="Patrick" last="Danoy">Patrick Danoy</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kemp, John P" sort="Kemp, John P" uniqKey="Kemp J" first="John P." last="Kemp">John P. Kemp</name><affiliation><nlm:aff id="aff2"><addr-line>Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Leo, Paul J" sort="Leo, Paul J" uniqKey="Leo P" first="Paul J." last="Leo">Paul J. Leo</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Mccloskey, Eugene" sort="Mccloskey, Eugene" uniqKey="Mccloskey E" first="Eugene" last="Mccloskey">Eugene Mccloskey</name><affiliation><nlm:aff id="aff3"><addr-line>Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nicholson, Geoffrey C" sort="Nicholson, Geoffrey C" uniqKey="Nicholson G" first="Geoffrey C." last="Nicholson">Geoffrey C. Nicholson</name><affiliation><nlm:aff id="aff4"><addr-line>The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eastell, Richard" sort="Eastell, Richard" uniqKey="Eastell R" first="Richard" last="Eastell">Richard Eastell</name><affiliation><nlm:aff id="aff3"><addr-line>Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, Sheffield, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Prince, Richard L" sort="Prince, Richard L" uniqKey="Prince R" first="Richard L." last="Prince">Richard L. Prince</name><affiliation><nlm:aff id="aff5"><addr-line>School of Medicine and Pharmacology, University of Western Australia, Perth, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff6"><addr-line>Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Eisman, John A" sort="Eisman, John A" uniqKey="Eisman J" first="John A." last="Eisman">John A. Eisman</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>St. Vincent's Clinical School, St. Vincent's Hospital Campus, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Jones, Graeme" sort="Jones, Graeme" uniqKey="Jones G" first="Graeme" last="Jones">Graeme Jones</name><affiliation><nlm:aff id="aff9"><addr-line>Menzies Research Institute, University of Tasmania, Hobart, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Sambrook, Philip N" sort="Sambrook, Philip N" uniqKey="Sambrook P" first="Philip N." last="Sambrook">Philip N. Sambrook</name><affiliation><nlm:aff id="aff10"><addr-line>Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reid, Ian R" sort="Reid, Ian R" uniqKey="Reid I" first="Ian R." last="Reid">Ian R. Reid</name><affiliation><nlm:aff id="aff11"><addr-line>Department of Medicine, University of Auckland, Auckland, New Zealand</addr-line></nlm:aff></affiliation></author><author><name sortKey="Dennison, Elaine M" sort="Dennison, Elaine M" uniqKey="Dennison E" first="Elaine M." last="Dennison">Elaine M. Dennison</name><affiliation><nlm:aff id="aff12"><addr-line>Medical Research Council Lifecourse Epidemiology Unit, Southampton, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Wark, John" sort="Wark, John" uniqKey="Wark J" first="John" last="Wark">John Wark</name><affiliation><nlm:aff id="aff13"><addr-line>University of Melbourne Department of Medicine and Bone and Mineral Service, Royal Melbourne Hospital, Melbourne, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Richards, J Brent" sort="Richards, J Brent" uniqKey="Richards J" first="J. Brent" last="Richards">J. Brent Richards</name><affiliation><nlm:aff id="aff14"><addr-line>Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff15"><addr-line>Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Uitterlinden, Andre G" sort="Uitterlinden, Andre G" uniqKey="Uitterlinden A" first="Andre G." last="Uitterlinden">Andre G. Uitterlinden</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Spector, Tim D" sort="Spector, Tim D" uniqKey="Spector T" first="Tim D." last="Spector">Tim D. Spector</name><affiliation><nlm:aff id="aff15"><addr-line>Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Esapa, Chris" sort="Esapa, Chris" uniqKey="Esapa C" first="Chris" last="Esapa">Chris Esapa</name><affiliation><nlm:aff id="aff17"><addr-line>Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, Oxfordshire, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff18"><addr-line>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cox, Roger D" sort="Cox, Roger D" uniqKey="Cox R" first="Roger D." last="Cox">Roger D. Cox</name><affiliation><nlm:aff id="aff17"><addr-line>Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, Oxfordshire, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brown, Steve D M" sort="Brown, Steve D M" uniqKey="Brown S" first="Steve D. M." last="Brown">Steve D. M. Brown</name><affiliation><nlm:aff id="aff17"><addr-line>Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, Oxfordshire, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Thakker, Rajesh V" sort="Thakker, Rajesh V" uniqKey="Thakker R" first="Rajesh V." last="Thakker">Rajesh V. Thakker</name><affiliation><nlm:aff id="aff18"><addr-line>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Addison, Kathryn A" sort="Addison, Kathryn A" uniqKey="Addison K" first="Kathryn A." last="Addison">Kathryn A. Addison</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Bradbury, Linda A" sort="Bradbury, Linda A" uniqKey="Bradbury L" first="Linda A." last="Bradbury">Linda A. Bradbury</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Center, Jacqueline R" sort="Center, Jacqueline R" uniqKey="Center J" first="Jacqueline R." last="Center">Jacqueline R. Center</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>St. Vincent's Clinical School, St. Vincent's Hospital Campus, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cooper, Cyrus" sort="Cooper, Cyrus" uniqKey="Cooper C" first="Cyrus" last="Cooper">Cyrus Cooper</name><affiliation><nlm:aff id="aff12"><addr-line>Medical Research Council Lifecourse Epidemiology Unit, Southampton, United Kingdom</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>National Institute for Health and Research Biomedical Research Unit, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Cremin, Catherine" sort="Cremin, Catherine" uniqKey="Cremin C" first="Catherine" last="Cremin">Catherine Cremin</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Estrada, Karol" sort="Estrada, Karol" uniqKey="Estrada K" first="Karol" last="Estrada">Karol Estrada</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Felsenberg, Dieter" sort="Felsenberg, Dieter" uniqKey="Felsenberg D" first="Dieter" last="Felsenberg">Dieter Felsenberg</name><affiliation><nlm:aff id="aff20"><addr-line>Centre of Muscle and Bone Research, Charité – University Medicine Berlin, Campus Benjamin Franklin, Free and Humboldt University, Berlin, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Gluer, Claus C" sort="Gluer, Claus C" uniqKey="Gluer C" first="Claus-C." last="Glüer">Claus-C. Glüer</name><affiliation><nlm:aff id="aff21"><addr-line>Medizinische Physik, Klinik für Diagnostische Radiologie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hadler, Johanna" sort="Hadler, Johanna" uniqKey="Hadler J" first="Johanna" last="Hadler">Johanna Hadler</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Henry, Margaret J" sort="Henry, Margaret J" uniqKey="Henry M" first="Margaret J." last="Henry">Margaret J. Henry</name><affiliation><nlm:aff id="aff22"><addr-line>School of Medicine, Deakin University, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Hofman, Albert" sort="Hofman, Albert" uniqKey="Hofman A" first="Albert" last="Hofman">Albert Hofman</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Kotowicz, Mark A" sort="Kotowicz, Mark A" uniqKey="Kotowicz M" first="Mark A." last="Kotowicz">Mark A. Kotowicz</name><affiliation><nlm:aff id="aff23"><addr-line>Department of Endocrinology and Diabetes, Barwon Health, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Makovey, Joanna" sort="Makovey, Joanna" uniqKey="Makovey J" first="Joanna" last="Makovey">Joanna Makovey</name><affiliation><nlm:aff id="aff24"><addr-line>Institute of Bone Joint Research, University of Sydney, Royal North Shore Hospital, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nguyen, Sing C" sort="Nguyen, Sing C" uniqKey="Nguyen S" first="Sing C." last="Nguyen">Sing C. Nguyen</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Nguyen, Tuan V" sort="Nguyen, Tuan V" uniqKey="Nguyen T" first="Tuan V." last="Nguyen">Tuan V. Nguyen</name><affiliation><nlm:aff id="aff7"><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff8"><addr-line>St. Vincent's Clinical School, St. Vincent's Hospital Campus, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff25"><addr-line>School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pasco, Julie A" sort="Pasco, Julie A" uniqKey="Pasco J" first="Julie A." last="Pasco">Julie A. Pasco</name><affiliation><nlm:aff id="aff22"><addr-line>School of Medicine, Deakin University, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Pryce, Karena" sort="Pryce, Karena" uniqKey="Pryce K" first="Karena" last="Pryce">Karena Pryce</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Reid, David M" sort="Reid, David M" uniqKey="Reid D" first="David M." last="Reid">David M. Reid</name><affiliation><nlm:aff id="aff26"><addr-line>Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Rivadeneira, Fernando" sort="Rivadeneira, Fernando" uniqKey="Rivadeneira F" first="Fernando" last="Rivadeneira">Fernando Rivadeneira</name><affiliation><nlm:aff id="aff16"><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></nlm:aff></affiliation></author><author><name sortKey="Roux, Christian" sort="Roux, Christian" uniqKey="Roux C" first="Christian" last="Roux">Christian Roux</name><affiliation><nlm:aff id="aff27"><addr-line>Rheumatology Department, AP-HP Cochin Hospital – Paris-Descartes University, Paris, France</addr-line></nlm:aff></affiliation></author><author><name sortKey="Stefansson, Kari" sort="Stefansson, Kari" uniqKey="Stefansson K" first="Kari" last="Stefansson">Kari Stefansson</name><affiliation><nlm:aff id="aff28"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff29"><addr-line>University of Iceland, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Styrkarsdottir, Unnur" sort="Styrkarsdottir, Unnur" uniqKey="Styrkarsdottir U" first="Unnur" last="Styrkarsdottir">Unnur Styrkarsdottir</name><affiliation><nlm:aff id="aff28"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Thorleifsson, Gudmar" sort="Thorleifsson, Gudmar" uniqKey="Thorleifsson G" first="Gudmar" last="Thorleifsson">Gudmar Thorleifsson</name><affiliation><nlm:aff id="aff28"><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></nlm:aff></affiliation></author><author><name sortKey="Tichawangana, Rumbidzai" sort="Tichawangana, Rumbidzai" uniqKey="Tichawangana R" first="Rumbidzai" last="Tichawangana">Rumbidzai Tichawangana</name><affiliation><nlm:aff id="aff4"><addr-line>The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health, Geelong, Australia</addr-line></nlm:aff></affiliation></author><author><name sortKey="Evans, David M" sort="Evans, David M" uniqKey="Evans D" first="David M." last="Evans">David M. Evans</name><affiliation><nlm:aff id="aff2"><addr-line>Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom</addr-line></nlm:aff></affiliation></author><author><name sortKey="Brown, Matthew A" sort="Brown, Matthew A" uniqKey="Brown M" first="Matthew A." last="Brown">Matthew A. Brown</name><affiliation><nlm:aff id="aff1"><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></nlm:aff></affiliation><affiliation><nlm:aff id="aff19"><addr-line>National Institute for Health and Research Biomedical Research Unit, University of Oxford, Oxford, United Kingdom</addr-line></nlm:aff></affiliation></author></analytic><series><title level="j">PLoS Genetics</title><idno type="ISSN">1553-7390</idno><idno type="eISSN">1553-7404</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low
bone mineral density (BMD) is a major predisposing factor to fracture and is
known to be highly heritable. Site-, gender-, and age-specific genetic effects
on BMD are thought to be significant, but have largely not been considered in
the design of genome-wide association studies (GWAS) of BMD to date. We report
here a GWAS using a novel study design focusing on women of a specific age
(postmenopausal women, age 55–85 years), with either extreme high or low
hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0,
n = 1055, or −4.0 to −1.5,
n = 900), with replication in cohorts of women drawn from
the general population (n = 20,898). The study replicates
21 of 26 known BMD–associated genes. Additionally, we report suggestive
association of a further six new genetic associations in or around the genes
<italic>CLCN7, GALNT3, IBSP, LTBP3, RSPO3</italic>, and
<italic>SOX4</italic>, with replication in two independent datasets. A novel
mouse model with a loss-of-function mutation in <italic>GALNT3</italic> is also
reported, which has high bone mass, supporting the involvement of this gene in
BMD determination. In addition to identifying further genes associated with BMD,
this study confirms the efficiency of extreme-truncate selection designs for
quantitative trait association studies.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Johnell, O" uniqKey="Johnell O">O Johnell</name></author><author><name sortKey="Kanis, Ja" uniqKey="Kanis J">JA Kanis</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kanis, Ja" uniqKey="Kanis J">JA Kanis</name></author><author><name sortKey="Johnell, O" uniqKey="Johnell O">O Johnell</name></author><author><name sortKey="Oden, A" uniqKey="Oden A">A Oden</name></author><author><name sortKey="Johansson, H" uniqKey="Johansson H">H Johansson</name></author><author><name sortKey="Mccloskey, E" uniqKey="Mccloskey E">E McCloskey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Henry, Mj" uniqKey="Henry M">MJ Henry</name></author><author><name sortKey="Pasco, Ja" uniqKey="Pasco J">JA Pasco</name></author><author><name sortKey="Seeman, E" uniqKey="Seeman E">E Seeman</name></author><author><name sortKey="Nicholson, Gc" uniqKey="Nicholson G">GC Nicholson</name></author><author><name sortKey="Sanders, Km" uniqKey="Sanders K">KM Sanders</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nguyen, Nd" uniqKey="Nguyen N">ND Nguyen</name></author><author><name sortKey="Pongchaiyakul, C" uniqKey="Pongchaiyakul C">C Pongchaiyakul</name></author><author><name sortKey="Center, Jr" uniqKey="Center J">JR Center</name></author><author><name sortKey="Eisman, Ja" uniqKey="Eisman J">JA Eisman</name></author><author><name sortKey="Nguyen, Tv" uniqKey="Nguyen T">TV Nguyen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Arden, Nk" uniqKey="Arden N">NK Arden</name></author><author><name sortKey="Baker, J" uniqKey="Baker J">J Baker</name></author><author><name sortKey="Hogg, C" uniqKey="Hogg C">C Hogg</name></author><author><name sortKey="Baan, K" uniqKey="Baan K">K 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uniqKey="Howard G">GM Howard</name></author><author><name sortKey="Kelly, Pj" uniqKey="Kelly P">PJ Kelly</name></author><author><name sortKey="Eisman, Ja" uniqKey="Eisman J">JA Eisman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nguyen, Tv" uniqKey="Nguyen T">TV Nguyen</name></author><author><name sortKey="Howard, Gm" uniqKey="Howard G">GM Howard</name></author><author><name sortKey="Kelly, Pj" uniqKey="Kelly P">PJ Kelly</name></author><author><name sortKey="Eisman, Ja" uniqKey="Eisman J">JA Eisman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Duncan, E" uniqKey="Duncan E">E Duncan</name></author><author><name sortKey="Cardon, L" uniqKey="Cardon L">L Cardon</name></author><author><name sortKey="Sinsheimer, J" uniqKey="Sinsheimer J">J Sinsheimer</name></author><author><name sortKey="Wass, J" uniqKey="Wass J">J Wass</name></author><author><name sortKey="Brown, M" uniqKey="Brown M">M 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uniqKey="Bahlo M">M Bahlo</name></author><author><name sortKey="Stankovich, J" uniqKey="Stankovich J">J Stankovich</name></author><author><name sortKey="Danoy, P" uniqKey="Danoy P">P Danoy</name></author><author><name sortKey="Hickey, Pf" uniqKey="Hickey P">PF Hickey</name></author><author><name sortKey="Taylor, Bv" uniqKey="Taylor B">BV Taylor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Richards, Jb" uniqKey="Richards J">JB Richards</name></author><author><name sortKey="Rivadeneira, F" uniqKey="Rivadeneira F">F Rivadeneira</name></author><author><name sortKey="Inouye, M" uniqKey="Inouye M">M Inouye</name></author><author><name sortKey="Pastinen, Tm" uniqKey="Pastinen T">TM Pastinen</name></author><author><name sortKey="Soranzo, N" uniqKey="Soranzo N">N Soranzo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Styrkarsdottir, U" uniqKey="Styrkarsdottir U">U Styrkarsdottir</name></author><author><name sortKey="Halldorsson, Bv" uniqKey="Halldorsson B">BV Halldorsson</name></author><author><name sortKey="Gretarsdottir, S" uniqKey="Gretarsdottir S">S Gretarsdottir</name></author><author><name sortKey="Gudbjartsson, Df" uniqKey="Gudbjartsson D">DF Gudbjartsson</name></author><author><name sortKey="Walters, Gb" uniqKey="Walters G">GB Walters</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Styrkarsdottir, U" uniqKey="Styrkarsdottir U">U Styrkarsdottir</name></author><author><name sortKey="Halldorsson, Bv" uniqKey="Halldorsson B">BV Halldorsson</name></author><author><name sortKey="Gretarsdottir, S" uniqKey="Gretarsdottir S">S Gretarsdottir</name></author><author><name sortKey="Gudbjartsson, Df" uniqKey="Gudbjartsson D">DF Gudbjartsson</name></author><author><name sortKey="Walters, Gb" uniqKey="Walters G">GB Walters</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shepherd, Ja" uniqKey="Shepherd J">JA 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosgen</journal-id><journal-title-group><journal-title>PLoS Genetics</journal-title></journal-title-group><issn pub-type="ppub">1553-7390</issn><issn pub-type="epub">1553-7404</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21533022</article-id><article-id pub-id-type="pmc">3080863</article-id><article-id pub-id-type="publisher-id">10-PLGE-RA-NV-4180R4</article-id><article-id pub-id-type="doi">10.1371/journal.pgen.1001372</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline"><subject>Diabetes and Endocrinology/Bone and Mineral Metabolism</subject><subject>Genetics and Genomics/Genetics of Disease</subject><subject>Rheumatology/Bone and Mineral Metabolism</subject></subj-group></article-categories><title-group><article-title>Genome-Wide Association Study Using Extreme Truncate Selection
Identifies Novel Genes Affecting Bone Mineral Density and Fracture
Risk</article-title><alt-title alt-title-type="running-head">Genetics of Osteoporosis</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Duncan</surname><given-names>Emma L.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Danoy</surname><given-names>Patrick</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kemp</surname><given-names>John P.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Leo</surname><given-names>Paul J.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>McCloskey</surname><given-names>Eugene</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nicholson</surname><given-names>Geoffrey C.</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Eastell</surname><given-names>Richard</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Prince</surname><given-names>Richard L.</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref><xref ref-type="aff" rid="aff6"><sup>6</sup></xref></contrib><contrib contrib-type="author"><name><surname>Eisman</surname><given-names>John A.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff8"><sup>8</sup></xref></contrib><contrib contrib-type="author"><name><surname>Jones</surname><given-names>Graeme</given-names></name><xref ref-type="aff" rid="aff9"><sup>9</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sambrook</surname><given-names>Philip N.</given-names></name><xref ref-type="aff" rid="aff10"><sup>10</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reid</surname><given-names>Ian R.</given-names></name><xref ref-type="aff" rid="aff11"><sup>11</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dennison</surname><given-names>Elaine M.</given-names></name><xref ref-type="aff" rid="aff12"><sup>12</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wark</surname><given-names>John</given-names></name><xref ref-type="aff" rid="aff13"><sup>13</sup></xref></contrib><contrib contrib-type="author"><name><surname>Richards</surname><given-names>J. 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rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hofman</surname><given-names>Albert</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kotowicz</surname><given-names>Mark A.</given-names></name><xref ref-type="aff" rid="aff23"><sup>23</sup></xref></contrib><contrib contrib-type="author"><name><surname>Makovey</surname><given-names>Joanna</given-names></name><xref ref-type="aff" rid="aff24"><sup>24</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nguyen</surname><given-names>Sing C.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Nguyen</surname><given-names>Tuan V.</given-names></name><xref ref-type="aff" rid="aff7"><sup>7</sup></xref><xref ref-type="aff" rid="aff8"><sup>8</sup></xref><xref ref-type="aff" rid="aff25"><sup>25</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pasco</surname><given-names>Julie A.</given-names></name><xref ref-type="aff" rid="aff22"><sup>22</sup></xref></contrib><contrib contrib-type="author"><name><surname>Pryce</surname><given-names>Karena</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Reid</surname><given-names>David M.</given-names></name><xref ref-type="aff" rid="aff26"><sup>26</sup></xref></contrib><contrib contrib-type="author"><name><surname>Rivadeneira</surname><given-names>Fernando</given-names></name><xref ref-type="aff" rid="aff16"><sup>16</sup></xref></contrib><contrib contrib-type="author"><name><surname>Roux</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff27"><sup>27</sup></xref></contrib><contrib contrib-type="author"><name><surname>Stefansson</surname><given-names>Kari</given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref><xref ref-type="aff" rid="aff29"><sup>29</sup></xref></contrib><contrib contrib-type="author"><name><surname>Styrkarsdottir</surname><given-names>Unnur</given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref></contrib><contrib contrib-type="author"><name><surname>Thorleifsson</surname><given-names>Gudmar</given-names></name><xref ref-type="aff" rid="aff28"><sup>28</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tichawangana</surname><given-names>Rumbidzai</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Evans</surname><given-names>David M.</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Brown</surname><given-names>Matthew A.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff19"><sup>19</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Medical Research Council Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Academic Unit of Bone Metabolism, Metabolic Bone Centre, University of Sheffield, Sheffield, United Kingdom</addr-line></aff><aff id="aff4"><label>4</label><addr-line>The University of Melbourne, Department of Clinical and Biomedical Sciences: Barwon Health, Geelong, Australia</addr-line></aff><aff id="aff5"><label>5</label><addr-line>School of Medicine and Pharmacology, University of Western Australia, Perth, Australia</addr-line></aff><aff id="aff6"><label>6</label><addr-line>Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia</addr-line></aff><aff id="aff7"><label>7</label><addr-line>Garvan Institute of Medical Research, Sydney, Australia</addr-line></aff><aff id="aff8"><label>8</label><addr-line>St. Vincent's Clinical School, St. Vincent's Hospital Campus, University of New South Wales, Sydney, Australia</addr-line></aff><aff id="aff9"><label>9</label><addr-line>Menzies Research Institute, University of Tasmania, Hobart, Australia</addr-line></aff><aff id="aff10"><label>10</label><addr-line>Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, Australia</addr-line></aff><aff id="aff11"><label>11</label><addr-line>Department of Medicine, University of Auckland, Auckland, New Zealand</addr-line></aff><aff id="aff12"><label>12</label><addr-line>Medical Research Council Lifecourse Epidemiology Unit, Southampton, United Kingdom</addr-line></aff><aff id="aff13"><label>13</label><addr-line>University of Melbourne Department of Medicine and Bone and Mineral Service, Royal Melbourne Hospital, Melbourne, Australia</addr-line></aff><aff id="aff14"><label>14</label><addr-line>Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada</addr-line></aff><aff id="aff15"><label>15</label><addr-line>Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom</addr-line></aff><aff id="aff16"><label>16</label><addr-line>Department of Internal Medicine and Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands</addr-line></aff><aff id="aff17"><label>17</label><addr-line>Medical Research Council Mammalian Genetics Unit, Harwell Science and Innovation Campus, Harwell, Oxfordshire, United Kingdom</addr-line></aff><aff id="aff18"><label>18</label><addr-line>Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford, United Kingdom</addr-line></aff><aff id="aff19"><label>19</label><addr-line>National Institute for Health and Research Biomedical Research Unit, University of Oxford, Oxford, United Kingdom</addr-line></aff><aff id="aff20"><label>20</label><addr-line>Centre of Muscle and Bone Research, Charité – University Medicine Berlin, Campus Benjamin Franklin, Free and Humboldt University, Berlin, Germany</addr-line></aff><aff id="aff21"><label>21</label><addr-line>Medizinische Physik, Klinik für Diagnostische Radiologie, Universitätsklinikum Schleswig-Holstein, Kiel, Germany</addr-line></aff><aff id="aff22"><label>22</label><addr-line>School of Medicine, Deakin University, Geelong, Australia</addr-line></aff><aff id="aff23"><label>23</label><addr-line>Department of Endocrinology and Diabetes, Barwon Health, Geelong, Australia</addr-line></aff><aff id="aff24"><label>24</label><addr-line>Institute of Bone Joint Research, University of Sydney, Royal North Shore Hospital, Sydney, Australia</addr-line></aff><aff id="aff25"><label>25</label><addr-line>School of Public Health and Community Medicine, University of New South Wales, Sydney, Australia</addr-line></aff><aff id="aff26"><label>26</label><addr-line>Division of Applied Medicine, University of Aberdeen, Aberdeen, United Kingdom</addr-line></aff><aff id="aff27"><label>27</label><addr-line>Rheumatology Department, AP-HP Cochin Hospital – Paris-Descartes University, Paris, France</addr-line></aff><aff id="aff28"><label>28</label><addr-line>deCODE Genetics, Reykjavik, Iceland</addr-line></aff><aff id="aff29"><label>29</label><addr-line>University of Iceland, Reykjavik, Iceland</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Gibson</surname><given-names>Greg</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">Georgia Institute of Technology, United States of America; David B. Allison, University of Alabama at Birmingham, United States of America</aff><author-notes><corresp id="cor1">* E-mail: <email>matt.brown@uq.edu.au</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: EL Duncan, P Danoy, E McCloskey, GC
Nicholson, R Eastell, RL Prince, JA Eisman, G Jones, JB Richards, AG
Uitterlinden, TD Spector, C Esapa, RD Cox, SDM Brown, RV Thakker, K Estrada,
F Rivadeneira, K Stafansson, U Styrkarsdottir, G Thorleifsson, MA Brown.
Performed the experiments: EL Duncan, P Danoy, C Esapa, RD Cox, KA Addison,
LA Bradbury, C Cremin, K Estrada, CC Glüer, J Hadler, K Pryce. Analyzed
the data: EL Duncan, P Danoy, JP Kemp, PJ Leo, JB Richards, AG Uitterlinden,
TD Spector, C Esapa, RD Cox, SDM Brown, RV Thakker, K Estrada, CC
Glüer, J Hadler, F Rivadeneira, K Stefansson, U Styrkarsdottir, G
Thorleifsson, DM Evans, MA Brown. Contributed reagents/materials/analysis
tools: EL Duncan, P Danoy, JP Kemp, PJ Leo, E McCloskey, GC Nicholson, R
Eastell, RLPrince, JA Eisman, G Jones, PN Sambrook, IR Reid, EM Dennison, J
Wark, JB Richards, AG Uitterlinden, TD Spector, C Esapa, SDM Brown, RV
Thakker, LA Bradbury, JR Center, C Cooper, K Estrada, D Felsenberg, CC
Glüer, MJ Henry, A Hofman, MA Kotowicz, J Makovey, SC Nguyen, TV
Nguyen, JA Pasco, DM Reid, F Rivadeneira, C Roux, K Stefansson, U
Styrkarsdottir, G Thorleifsson, R Tichawangana, DM Evans, MA Brown. Wrote
the paper: EL Duncan, PJ Leo, DM Evans, MA Brown.</p></fn></author-notes><pub-date pub-type="collection"><month>4</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>21</day><month>4</month><year>2011</year></pub-date><volume>7</volume><issue>4</issue><elocation-id>e1001372</elocation-id><history><date date-type="received"><day>16</day><month>9</month><year>2010</year></date><date date-type="accepted"><day>13</day><month>3</month><year>2011</year></date></history><permissions><copyright-statement>Duncan et al.</copyright-statement><copyright-year>2011</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><p>Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low
bone mineral density (BMD) is a major predisposing factor to fracture and is
known to be highly heritable. Site-, gender-, and age-specific genetic effects
on BMD are thought to be significant, but have largely not been considered in
the design of genome-wide association studies (GWAS) of BMD to date. We report
here a GWAS using a novel study design focusing on women of a specific age
(postmenopausal women, age 55–85 years), with either extreme high or low
hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0,
n = 1055, or −4.0 to −1.5,
n = 900), with replication in cohorts of women drawn from
the general population (n = 20,898). The study replicates
21 of 26 known BMD–associated genes. Additionally, we report suggestive
association of a further six new genetic associations in or around the genes
<italic>CLCN7, GALNT3, IBSP, LTBP3, RSPO3</italic>, and
<italic>SOX4</italic>, with replication in two independent datasets. A novel
mouse model with a loss-of-function mutation in <italic>GALNT3</italic> is also
reported, which has high bone mass, supporting the involvement of this gene in
BMD determination. In addition to identifying further genes associated with BMD,
this study confirms the efficiency of extreme-truncate selection designs for
quantitative trait association studies.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Osteoporotic fracture is a major cause of early mortality and morbidity in the
community. To identify genes associated with osteoporosis, we have performed a
genome-wide association study. In order to improve study power and to address
the demographic group of highest risk from osteoporotic fracture, we have used a
unique study design, studying 1,955 postmenopausal women with either extreme
high or low hip bone mineral density. We then confirmed our findings in 20,898
women from the general population. Our study replicated 21 of 26 known
osteoporosis genes, and it identified a further six novel loci (in or nearby
<italic>CLCN7, GALNT3, IBSP, LTBP3, RSPO3</italic>, and
<italic>SOX4</italic>). For one of these loci, <italic>GALTN3</italic>, we
demonstrate in a mouse model that a loss-of-function genetic mutation in
<italic>GALNT3</italic> causes high bone mass. These findings report novel
mechanisms by which osteoporosis can arise, and they significantly add to our
understanding of the aetiology of the disease.</p></abstract><counts><page-count count="10"></page-count></counts></article-meta></front><body><sec id="s1"><title>Introduction</title><p>Osteoporotic fracture is a leading cause of morbidity and mortality in the community,
particularly amongst the elderly. In 2004 ten million Americans were estimated to
have osteoporosis, resulting in 1.5 million fractures per annum <xref rid="pgen.1001372-US1" ref-type="bibr">[1]</xref>. Hip fracture is
associated with a one year mortality rate of 36% in men and 21% in
women <xref rid="pgen.1001372-US2" ref-type="bibr">[2]</xref>; and the
burden of disease of osteoporotic fractures overall is similar to that of colorectal
cancer and greater than that of hypertension and breast cancer <xref rid="pgen.1001372-Johnell1" ref-type="bibr">[3]</xref>. Bone mineral density (BMD) is
strongly correlated with bone strength and fracture risk, and its measurement is
widely used as a diagnostic tool in the assessment of fracture risk <xref rid="pgen.1001372-Kanis1" ref-type="bibr">[4]</xref>–<xref rid="pgen.1001372-Nguyen1" ref-type="bibr">[6]</xref>. BMD is known to
be highly heritable, with heritability assessed in both young and elderly twins, and
in families, to be 60–90% <xref rid="pgen.1001372-Arden1" ref-type="bibr">[7]</xref>–<xref rid="pgen.1001372-Flicker1" ref-type="bibr">[14]</xref>. Although the extent of
covariance between BMD and fracture risk is uncertain, of the 26 genes associated
with BMD at genome-wide significant levels to date, nine have been associated with
fracture risk (reviewed in <xref rid="pgen.1001372-Duncan2" ref-type="bibr">[15]</xref>), supporting the use of BMD as an intermediate phenotype
in the search for genes associated with fracture risk.</p><p>There is considerable evidence from genetic studies in humans <xref rid="pgen.1001372-Duncan1" ref-type="bibr">[12]</xref>, <xref rid="pgen.1001372-Naganathan1" ref-type="bibr">[16]</xref>, <xref rid="pgen.1001372-Rivadeneira1" ref-type="bibr">[17]</xref>, and in mice <xref rid="pgen.1001372-Orwoll1" ref-type="bibr">[18]</xref>, indicating
that the genes that influence BMD at different sites, and in the different genders,
overlap but are not identical. Thus far all genome-wide association studies (GWAS)
of BMD have studied cohorts of a wide age range, and with one exception have
included both men and women; when only women have been studied, both pre- and
postmenopausal women have been included. Therefore, to identify genes involved in
osteoporosis in the demographic at highest risk of osteoporotic fracture we have
performed a GWAS in postmenopausal women selected on the basis of their hip BMD, and
replicated the GWAS findings in a large cohort of adult women drawn from the general
population.</p></sec><sec id="s2"><title>Results</title><p>Considering markers previously reported as associated with BMD, our discovery dataset
replicates previously associated SNPs in 21 of the 26 genes reported to date to have
genome-wide significant associations (<xref ref-type="supplementary-material" rid="pgen.1001372.s009">Table S6</xref>) (P<0.05, association in the same
direction as initially reported, or, in the case of <italic>LRP5</italic> and
<italic>GPR177,</italic> with the next flanking SNP genotyped) <xref rid="pgen.1001372-Rivadeneira1" ref-type="bibr">[17]</xref>, <xref rid="pgen.1001372-Richards1" ref-type="bibr">[21]</xref>, <xref rid="pgen.1001372-Styrkarsdottir1" ref-type="bibr">[22]</xref>, <xref rid="pgen.1001372-Styrkarsdottir2" ref-type="bibr">[23]</xref>, <xref rid="pgen.1001372-Kung1" ref-type="bibr">[28]</xref>, <xref rid="pgen.1001372-Cho1" ref-type="bibr">[32]</xref>, <xref rid="pgen.1001372-Xiong1" ref-type="bibr">[33]</xref>, <xref rid="pgen.1001372-Timpson1" ref-type="bibr">[34]</xref>. Replicated
genes include <italic>ARHGAP1, CTNNB1, ESR1, FAM3C, FLJ42280, FOXL1, GPR177, HDAC5,
JAG1, LRP5, MARK3, MEF2C, MEPE, OPG, RANK, RANKL, SOST, SOX6, SP7</italic>(Osterix), <italic>STARD3NL</italic> and <italic>ZBTB40</italic>. Considering the
combined Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) and
deCODE/TwinsUK/Rotterdam cohorts, 97 SNPs from six loci achieved
P<5×10<sup>−8</sup> at the femoral neck (FN), of which four had
previously been reported (<italic>FLJ42280, MEF2C, SOX6, ZBTB40</italic>). At the
lumbar spine (LS), six SNPs from two known loci (<italic>RANKL, OPG)</italic>achieved P<5×10<sup>−8</sup>. No support was seen for previously
reported associations involving SNPs in <italic>ADAMTS18, CRHR1, DCDC5,
MHC,</italic> or <italic>SBTBN1</italic> (P>0.05).</p><p>This study also identifies and replicates two novel loci with confirmed association
with BMD in <italic>GALNT3</italic> (MIM: 601756) and at chromosome 6q22 near
<italic>RSPO3</italic> (MIM: 610574), and provides strong evidence of a further
four BMD-associated loci (<italic>CLCN7</italic> (MIM: 602727),
<italic>IBSP</italic> (MIM: 147563), <italic>LTBP3</italic> (MIM: 602090),
<italic>SOX4</italic> (MIM: 184430)) (<xref ref-type="table" rid="pgen-1001372-t001">Table 1</xref>). Although these did not achieve
‘genome-wide significance’ in the discovery set alone, they achieved
P-values in the AOGC-discovery cohort of P<10<sup>−4</sup>, and support in
the AOGC-replication cohort, TwinsUK, Rotterdam and deCODE cohorts; and all have
additional evidence supporting their role in bone. Support was also seen for
<italic>TGFBR3</italic> (MIM: 600742), a gene previously reported to have
suggestive association with BMD <xref rid="pgen.1001372-Xiong1" ref-type="bibr">[33]</xref>.</p><table-wrap id="pgen-1001372-t001" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1001372.t001</object-id><label>Table 1</label><caption><title>Findings for novel replicated associations.</title></caption><alternatives><graphic id="pgen-1001372-t001-1" xlink:href="pgen.1001372.t001"></graphic><table frame="hsides" rules="groups"><colgroup span="1"><col align="left" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col><col align="center" span="1"></col></colgroup><thead><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td colspan="6" align="left" rowspan="1">AOGC DISCOVERY</td><td colspan="4" align="left" rowspan="1">REPLICATION</td><td colspan="4" align="left" rowspan="1">COMBINED DISCOVERY/REPLICATION</td></tr><tr><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td align="left" rowspan="1" colspan="1"></td><td colspan="2" align="left" rowspan="1">TH</td><td colspan="2" align="left" rowspan="1">FN</td><td colspan="2" align="left" rowspan="1">LS</td><td colspan="2" align="left" rowspan="1">FN</td><td colspan="2" align="left" rowspan="1">LS</td><td colspan="2" align="left" rowspan="1">FN</td><td colspan="2" align="left" rowspan="1">LS</td></tr><tr><td align="left" rowspan="1" colspan="1">LOCUS</td><td align="left" rowspan="1" colspan="1">SNP</td><td align="left" rowspan="1" colspan="1">A1/A2</td><td align="left" rowspan="1" colspan="1">GENE</td><td align="left" rowspan="1" colspan="1">BETA</td><td align="left" rowspan="1" colspan="1">P-VALUE</td><td align="left" rowspan="1" colspan="1">BETA</td><td align="left" rowspan="1" colspan="1">P-VALUE</td><td align="left" rowspan="1" colspan="1">BETA</td><td align="left" rowspan="1" colspan="1">P-VALUE</td><td align="left" rowspan="1" colspan="1">BETA</td><td align="left" rowspan="1" colspan="1">P-VALUE</td><td align="left" rowspan="1" colspan="1">BETA</td><td align="left" rowspan="1" colspan="1">P-VALUE</td><td align="left" rowspan="1" colspan="1">BETA</td><td align="left" rowspan="1" colspan="1">P-VALUE</td><td align="left" rowspan="1" colspan="1">BETA</td><td align="left" rowspan="1" colspan="1">P-VALUE</td></tr></thead><tbody><tr><td align="left" rowspan="1" colspan="1">2q24</td><td align="left" rowspan="1" colspan="1">rs1863196</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1"><italic>GALNT3</italic></td><td align="left" rowspan="1" colspan="1">0.284</td><td align="left" rowspan="1" colspan="1">2.3×10<sup>-5</sup></td><td align="left" rowspan="1" colspan="1">−0.090</td><td align="left" rowspan="1" colspan="1">3.7×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.068</td><td align="left" rowspan="1" colspan="1">0.037</td><td align="left" rowspan="1" colspan="1">−0.065</td><td align="left" rowspan="1" colspan="1">0.0011</td><td align="left" rowspan="1" colspan="1">−0.01</td><td align="left" rowspan="1" colspan="1">0.72</td><td align="left" rowspan="1" colspan="1">−0.077</td><td align="left" rowspan="1" colspan="1">2.0×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">−0.024</td><td align="left" rowspan="1" colspan="1">0.16</td></tr><tr><td align="left" rowspan="1" colspan="1">2q24</td><td align="left" rowspan="1" colspan="1">rs6710518</td><td align="left" rowspan="1" colspan="1">C/T</td><td align="left" rowspan="1" colspan="1"><italic>GALNT3</italic></td><td align="left" rowspan="1" colspan="1">0.262</td><td align="left" rowspan="1" colspan="1">6.9×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.078</td><td align="left" rowspan="1" colspan="1">0.0015</td><td align="left" rowspan="1" colspan="1">−0.068</td><td align="left" rowspan="1" colspan="1">0.039</td><td align="left" rowspan="1" colspan="1">−0.057</td><td align="left" rowspan="1" colspan="1">1.2×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">−0.037</td><td align="left" rowspan="1" colspan="1">0.01</td><td align="left" rowspan="1" colspan="1">−0.064</td><td align="left" rowspan="1" colspan="1">4.8×10<sup>−10</sup></td><td align="left" rowspan="1" colspan="1">−0.042</td><td align="left" rowspan="1" colspan="1">0.0017</td></tr><tr><td align="left" rowspan="1" colspan="1">4q22</td><td align="left" rowspan="1" colspan="1">rs1054627</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1"><italic>IBSP</italic></td><td align="left" rowspan="1" colspan="1">0.277</td><td align="left" rowspan="1" colspan="1">6.6×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.042</td><td align="left" rowspan="1" colspan="1">0.00024</td><td align="left" rowspan="1" colspan="1">−0.049</td><td align="left" rowspan="1" colspan="1">0.18</td><td align="left" rowspan="1" colspan="1">−0.043</td><td align="left" rowspan="1" colspan="1">9.2×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.027</td><td align="left" rowspan="1" colspan="1">0.046</td><td align="left" rowspan="1" colspan="1">−0.050</td><td align="left" rowspan="1" colspan="1">7.6×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">−0.03</td><td align="left" rowspan="1" colspan="1">0.019</td></tr><tr><td align="left" rowspan="1" colspan="1">6p22</td><td align="left" rowspan="1" colspan="1">rs9466056</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1"><italic>SOX4</italic></td><td align="left" rowspan="1" colspan="1">−0.237</td><td align="left" rowspan="1" colspan="1">5.3×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">0.090</td><td align="left" rowspan="1" colspan="1">6.6×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">0.10</td><td align="left" rowspan="1" colspan="1">0.0036</td><td align="left" rowspan="1" colspan="1">0.033</td><td align="left" rowspan="1" colspan="1">0.0033</td><td align="left" rowspan="1" colspan="1">0.021</td><td align="left" rowspan="1" colspan="1">0.17</td><td align="left" rowspan="1" colspan="1">0.049</td><td align="left" rowspan="1" colspan="1">4.2×10<sup>−6</sup></td><td align="left" rowspan="1" colspan="1">0.035</td><td align="left" rowspan="1" colspan="1">0.014</td></tr><tr><td align="left" rowspan="1" colspan="1">6q22</td><td align="left" rowspan="1" colspan="1">rs17563605</td><td align="left" rowspan="1" colspan="1">T/C</td><td align="left" rowspan="1" colspan="1"><italic>RSPO3</italic></td><td align="left" rowspan="1" colspan="1">0.30</td><td align="left" rowspan="1" colspan="1">2.1×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">−0.10</td><td align="left" rowspan="1" colspan="1">7.4×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.088</td><td align="left" rowspan="1" colspan="1">0.020</td><td align="left" rowspan="1" colspan="1">−0.051</td><td align="left" rowspan="1" colspan="1">2.1×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">−0.047</td><td align="left" rowspan="1" colspan="1">0.0097</td><td align="left" rowspan="1" colspan="1">−0.062</td><td align="left" rowspan="1" colspan="1">2.5×10<sup>−7</sup></td><td align="left" rowspan="1" colspan="1">−0.055</td><td align="left" rowspan="1" colspan="1">0.00082</td></tr><tr><td align="left" rowspan="1" colspan="1">6q22</td><td align="left" rowspan="1" colspan="1">rs13204965</td><td align="left" rowspan="1" colspan="1">A/C</td><td align="left" rowspan="1" colspan="1"><italic>RSPO3</italic></td><td align="left" rowspan="1" colspan="1">0.30</td><td align="left" rowspan="1" colspan="1">2.1×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">−0.10</td><td align="left" rowspan="1" colspan="1">7.3×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.089</td><td align="left" rowspan="1" colspan="1">0.020</td><td align="left" rowspan="1" colspan="1">−0.057</td><td align="left" rowspan="1" colspan="1">3.5×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">−0.049</td><td align="left" rowspan="1" colspan="1">0.0082</td><td align="left" rowspan="1" colspan="1">−0.067</td><td align="left" rowspan="1" colspan="1">3.0×10<sup>−8</sup></td><td align="left" rowspan="1" colspan="1">−0.056</td><td align="left" rowspan="1" colspan="1">0.00067</td></tr><tr><td align="left" rowspan="1" colspan="1">11p13</td><td align="left" rowspan="1" colspan="1">rs1152620</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1"><italic>LTBP3</italic></td><td align="left" rowspan="1" colspan="1">−0.311</td><td align="left" rowspan="1" colspan="1">4.4×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">0.060</td><td align="left" rowspan="1" colspan="1">0.020</td><td align="left" rowspan="1" colspan="1">0.080</td><td align="left" rowspan="1" colspan="1">0.041</td><td align="left" rowspan="1" colspan="1">0.039</td><td align="left" rowspan="1" colspan="1">0.0051</td><td align="left" rowspan="1" colspan="1">0.013</td><td align="left" rowspan="1" colspan="1">0.48</td><td align="left" rowspan="1" colspan="1">0.044</td><td align="left" rowspan="1" colspan="1">3.6×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">0.025</td><td align="left" rowspan="1" colspan="1">0.13</td></tr><tr><td align="left" rowspan="1" colspan="1">16p13</td><td align="left" rowspan="1" colspan="1">rs13336428</td><td align="left" rowspan="1" colspan="1">A/G</td><td align="left" rowspan="1" colspan="1"><italic>CLCN7</italic></td><td align="left" rowspan="1" colspan="1">−0.221</td><td align="left" rowspan="1" colspan="1">7.0×10<sup>−4</sup></td><td align="left" rowspan="1" colspan="1">0.057</td><td align="left" rowspan="1" colspan="1">0.013</td><td align="left" rowspan="1" colspan="1">0.076</td><td align="left" rowspan="1" colspan="1">0.028</td><td align="left" rowspan="1" colspan="1">0.040</td><td align="left" rowspan="1" colspan="1">0.0011</td><td align="left" rowspan="1" colspan="1">0.045</td><td align="left" rowspan="1" colspan="1">0.0050</td><td align="left" rowspan="1" colspan="1">0.044</td><td align="left" rowspan="1" colspan="1">5.1×10<sup>−5</sup></td><td align="left" rowspan="1" colspan="1">0.051</td><td align="left" rowspan="1" colspan="1">5.1×10<sup>−4</sup></td></tr></tbody></table></alternatives><table-wrap-foot><fn id="nt101"><label></label><p>Findings for novel replicated associations for the AOGC discovery and
replication sets, combined replication sets (AOGC
replication/TwinsUK/Rotterdam/deCODE) and entire dataset (AOGC discovery
and replication/TwinsUK/Rotterdam/deCODE). The regression coefficient in
the TH analysis shows the expected increase in the log odds ratio of low
BMD per addition of allele A2. The regression coefficients in the FN and
LS analyses refer to the expected increase in standardized BMD per
addition of allele A2.</p></fn></table-wrap-foot></table-wrap><sec id="s2a"><title><italic>GALNT3</italic></title><p>SNPs at chromosome 2q24, in and around <italic>GALNT3</italic>, achieved near
genome-wide significance in our discovery cohort (peak P-value rs1863196, total
hip (TH) P = 2.3×10<sup>−5</sup>; LS
P = 0.037) (<xref ref-type="fig" rid="pgen-1001372-g001">Figure 1A</xref>). This SNP was not typed or imputed by either the
Rotterdam or the TwinsUK cohorts, but a nearby SNP showed strong association in
both AOGC and the combined replication cohorts (rs6710518; AOGC discovery, TH
P = 6.9×10<sup>−5</sup>; combined
replication sets, FN P = 2.7×10<sup>−7</sup>).
In the combined datasets the finding achieved genome-wide significance at the FN
(P = 1.7×10<sup>−10</sup>). Strong
association was also seen with this SNP at LS
(P = 7.5×10<sup>−5</sup>). Another marker
within <italic>GALNT3</italic>, rs4667492, was also associated with fracture
risk, including vertebral fractures (OR = 0.89;
95%CI = 0.80–0.99;
P = 0.032) and overall low trauma fractures
(OR = 0.92;
95%CI = 0.85–0.99;
P = 0.024).</p><fig id="pgen-1001372-g001" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1001372.g001</object-id><label>Figure 1</label><caption><title>SNP association plots for BMD-associated regions.</title><p>Discovery cohort association significance level is plotted against the
left hand y-axis as -log10(P-values). Genetic coordinates are as per
NCBI build 36.1. Filled circles represent genotyped SNPs, and outlined
diamonds represent imputed SNPs. The recombination rate (cM/Mb as per
HapMap data) is indicated by the purple dotted line and right hand
y-axis. Genes and ESTs are indicated with their approximate sizes and
direction of translation. (A) Chromosome 2q24 - <italic>GALNT3</italic>region. SNP association plot of findings from TH case-control analysis
of AOGC discovery set for a 500 kb region (166,100 kb to 166,600 kb) of
chromosome 2. LD is indicated by colour scale in relationship to marker
rs1863196. (B) Chromosome 6q22 - <italic>RSPO3</italic> region. SNP
association plot of findings from TH case-control analysis of AOGC
discovery set for a 1,200 kb region (126,600 kb to 127,800 kb) of
chromosome 6. LD is indicated by colour scale in relationship to marker
rs13204965.</p></caption><graphic xlink:href="pgen.1001372.g001"></graphic></fig><p>We have recently identified a mouse with an
<italic>N</italic>-ethyl-<italic>N</italic>-nitrosourea induced
loss-of-function <italic>GALNT3</italic> mutation (Trp589Arg), that develops
hyperphosphataemia with extraskeletal calcium deposition, and hence represents a
model for FTC <xref rid="pgen.1001372-Esapa1" ref-type="bibr">[35]</xref>. To establish further the association of
<italic>GALNT3</italic> and BMD, we determined BMD in these
<italic>GALNT3</italic> mutant mice. This revealed that homozygous
(−/−) <italic>GALNT3</italic> mutant male and female adult mice had
a higher areal BMD than their wild-type (+/+) litter mates, with
heterozygous (+/−) mice having intermediate BMD (<xref ref-type="fig" rid="pgen-1001372-g002">Figure 2</xref>). This loss-of-function
<italic>GALNT3</italic> mutation is predicted to lead to a reduced
glycosylation of FGF23, which increases its breakdown and leads to reduced serum
FGF23 concentrations <xref rid="pgen.1001372-Esapa1" ref-type="bibr">[35]</xref>.</p><fig id="pgen-1001372-g002" position="float"><object-id pub-id-type="doi">10.1371/journal.pgen.1001372.g002</object-id><label>Figure 2</label><caption><title>Areal BMD derived from DEXA analysis of 15- to 16-week-old
<italic>GALNT3</italic> mutant and wild-type mice.</title><p>P-values refer to Student t-test for two-way ANOVA across the three
genotypes.</p></caption><graphic xlink:href="pgen.1001372.g002"></graphic></fig></sec><sec id="s2b"><title><italic>RSPO3</italic></title><p>A novel genome-wide significant association was also seen at markers on
chromosome 6q22-23 (<xref ref-type="fig" rid="pgen-1001372-g001">Figure
1B</xref>). In the combined dataset, marker rs13204965 achieved genome-wide
significance at this locus at the FN
(P = 2.2×10<sup>−9</sup>), with strong
support in both the AOGC discovery set, and the combined replication sets
(AOGC-discovery, TH P = 2.1×10<sup>−4</sup>;
combined replication P = 3.5×10<sup>−5</sup>).
Strong association was also seen with LS BMD (rs13204965
P = 0.00067). The peak of association at this locus lies
within a cDNA fragment, AK127472. The nearest gene, <italic>RSPO3</italic>(R-spondin-3), is 275 kb telomeric of the strongest associated SNP, but is
within the associated linkage disequilibrium region (<xref ref-type="fig" rid="pgen-1001372-g001">Figure 1B</xref>).</p></sec><sec id="s2c"><title><italic>CLCN7</italic></title><p>Association was observed at chromosome 16p13 with SNPs in and around
<italic>CLCN7</italic>, which encodes a
Cl<sup>−</sup>/H<sup>+</sup> antiporter expressed primarily in
osteoclasts, and critical to lysosomal acidification, an essential process in
bone resorption. Peak association at this locus was seen with SNP rs13336428 in
the discovery set (TH P = 7.0×10<sup>−4</sup>;
LS P = 0.028) (<xref ref-type="supplementary-material" rid="pgen.1001372.s003">Figure S3A</xref>), which was confirmed in the
replication set (FN P = 3.6×10<sup>−5</sup>; LS
P = 0.00012), achieving
P = 1.7×10<sup>−6</sup> at the FN and
1.2×10<sup>−5</sup> at LS in the overall cohort. Association has
previously been reported between two SNPs in exon 15 of <italic>CLCN7</italic>(rs12926089, rs12926669) and FN BMD (P = 0.001–0.003)
<xref rid="pgen.1001372-Pettersson1" ref-type="bibr">[36]</xref>;
no association was seen with either of those SNPs in the current study (P>0.4
at FN and LS).</p></sec><sec id="s2d"><title><italic>IBSP</italic></title><p>Association was observed with SNPs in <italic>IBSP</italic> (integrin-binding
bone sialoprotein) (<xref ref-type="supplementary-material" rid="pgen.1001372.s003">Figure S3B</xref>), encoded at chromosome 4q22, a
gene which has previously had suggestive association reported with BMD in two
studies (rs1054627, Styrkarrsdottir et al
P = 4.6×10<sup>−5</sup><xref rid="pgen.1001372-Styrkarsdottir1" ref-type="bibr">[22]</xref>;
Koller et al P = 1.5×10<sup>−4</sup><xref rid="pgen.1001372-Koller1" ref-type="bibr">[37]</xref>). In the
current study, moderate association was observed in the discovery set with the
same SNP as previously reported (rs1054627, AOGC discovery TH,
P = 6.6×10<sup>−5</sup>), with support in
the replication set and strong association overall (FN combined replication
P = 9.2×10<sup>−5</sup>; FN overall
association P = 7.6×10<sup>−7</sup>). Nominal
association was observed at LS (rs1054627, P = 0.019).</p></sec><sec id="s2e"><title><italic>LTBP3</italic></title><p>Association with BMD was also seen at chromosome 11p13, with SNP rs1152620
achieving P = 4.4×10<sup>−5</sup> (TH) in the
discovery set, P = 0.0051 (FN) in the replication set, and
P = 3.6×10<sup>−4</sup> overall (<xref ref-type="supplementary-material" rid="pgen.1001372.s003">Figure
S3C</xref>). This SNP was also nominally associated with LS BMD in the discovery
set (P = 0.041). The nearest gene to this locus is
<italic>LTBP3</italic> (latent transforming growth factor beta binding
protein 3), which is located 292 kb q-telomeric of rs1152620.</p></sec><sec id="s2f"><title><italic>SOX4</italic></title><p>At chromosome 6p22, SNPs in and around <italic>SOX4</italic> (Sex determining
region Y box 4) were moderately associated with BMD in our discovery set (most
significant association rs9466056, TH
P = 5.3×10<sup>−4</sup>; LS
P = 0.0036) (<xref ref-type="supplementary-material" rid="pgen.1001372.s003">Figure S3D</xref>), with support at the hip and LS
in the replication set (FN P = 0.00013, LS
P = 0.013), achieving association overall with
P = 2.6×10<sup>−7</sup> (FN) and
P = 0.00081 (LS).</p></sec></sec><sec id="s3"><title>Discussion</title><p>This study demonstrates convincing evidence of association with six genes with BMD
variation, <italic>GALNT3, RSPO3, CLCN7, IBSP, LTBP3</italic> and
<italic>SOX4</italic>. Using a moderate sample size, the use of a novel study
design also led to the confirmation of 21 of 26 known BMD-associations. This study
thus demonstrates the power of extreme-truncate selection designs for association
studies of quantitative traits.</p><p><italic>GALNT3</italic> encodes N-acetylgalactosaminyltransferase 3, an enzyme
involved in 0-glycosylation of serine and threonine residues. Mutations of
<italic>GALNT3</italic> are known to cause familial tumoral calcinosis (FTC,
OMIM 2111900) <xref rid="pgen.1001372-Topaz1" ref-type="bibr">[38]</xref>and hyperostosis-hyperphosphataemia syndrome (HOHP, OMIM 610233) <xref rid="pgen.1001372-Frishberg1" ref-type="bibr">[39]</xref>. FTC is
characterised by hyperphosphataemia in association with the deposition of calcium
phosphate crystals in extraskeletal tissues; whereas in HOHP, hyperphosphataemia is
associated with recurrent painful long bone swelling and radiographic evidence of
periosteal reaction and cortical hyperostosis. <italic>FGF23</italic> mutations
associated with FTC cause hyperphosphataemia through effects on expression of the
sodium-phosphate co-transporter in the kidney and small intestine, and through
increased activation of vitamin D due to increased renal expression of CYP27B1
(25-hydroxyvitamin-D 1 alpha hydroxylase) <xref rid="pgen.1001372-Larsson1" ref-type="bibr">[40]</xref>. It is unclear whether FGF23
has direct effects on the skeleton or if its effects are mediated through its
effects on serum phosphate and vitamin D levels. FGF23 signals via a complex of an
FGF receptor (FGFR1(IIIc)) and Klotho <xref rid="pgen.1001372-Urakawa1" ref-type="bibr">[41]</xref>; mice with a loss-of-function
mutation in <italic>Klotho</italic> develop osteoporosis amongst other
abnormalities, and modest evidence of association of <italic>Klotho</italic> with
BMD has been reported in several studies <xref rid="pgen.1001372-Kawano1" ref-type="bibr">[42]</xref>, <xref rid="pgen.1001372-Ogata1" ref-type="bibr">[43]</xref>, <xref rid="pgen.1001372-Riancho1" ref-type="bibr">[44]</xref>, <xref rid="pgen.1001372-Yamada1" ref-type="bibr">[45]</xref>. We saw no association with
polymorphisms in <italic>Klotho</italic> and BMD in the current study (P>0.05 for
all SNPs in and surrounding <italic>Klotho</italic>). To our knowledge, this finding
is the first demonstration in humans that genetic variants in the FGF23 pathway are
associated with any common human disease.</p><p><italic>RSPO3</italic> is one of four members of the R-spondin family (R-spondin-1 to
−4), which are known to activate the Wnt pathway, particularly through effects
on LRP6, itself previously reported to be BMD-associated <xref rid="pgen.1001372-Sims1" ref-type="bibr">[46]</xref>, <xref rid="pgen.1001372-vanMeurs1" ref-type="bibr">[47]</xref>. LRP6 is inhibited by the
proteins Kremen and DKK1, which combine to induce endocytosis of LRP6, reducing its
cell surface levels. R-spondin family members have been shown to disrupt
DKK1-dependent association of LRP6 and Kremen, thereby releasing LRP6 from this
inhibitory pathway <xref rid="pgen.1001372-Kim1" ref-type="bibr">[48]</xref>. R-spondin-4 mutations cause anonychia (absence or severe
hypoplasia of all fingernails and toenails, OMIM 206800) <xref rid="pgen.1001372-Blaydon1" ref-type="bibr">[49]</xref>. No human disease has been
associated with R-spondin-3, and knockout of R-spondin-3 in mice is embryonically
lethal due to defective placental development <xref rid="pgen.1001372-Aoki1" ref-type="bibr">[50]</xref>.</p><p>Mutations of <italic>CLCN7</italic> cause a family of osteopetroses of differing age
of presentation and severity, including infantile malignant
<italic>CLCN7</italic>-related recessive osteopetrosis (ARO), intermediate autosomal
osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII,
Albers-Schoenberg disease). These conditions are characterized by expanded, dense
bones, with markedly reduced bone resorption. Our data support associations of
polymorphisms at this locus with BMD variation in the population.</p><p>IBSP is a major non-collagenous bone matrix protein involved in calcium and
hydroxyapatite binding, and is thought to play a role in cell-matrix interactions
through RGD motifs in its amino acid sequence. IBSP is expressed in all major bone
cells including osteoblasts, osteocytes and osteoclasts; and its expression is
upregulated in osteoporotic bone <xref rid="pgen.1001372-Trost1" ref-type="bibr">[51]</xref>. <italic>IBSP</italic> knockout mice have low cortical
but high trabecular bone volume, with impaired bone formation, resorption, and
mineralization <xref rid="pgen.1001372-Malaval1" ref-type="bibr">[52]</xref>. <italic>IBSP</italic> lies within a cluster of genes
including <italic>DMP1, MEPE</italic>, and <italic>SPP1,</italic> all of which have
known roles in bone and are strong candidate genes for association with BMD.
<italic>MEPE</italic> has previously been associated with BMD at genome-wide
significance <xref rid="pgen.1001372-Rivadeneira1" ref-type="bibr">[17]</xref>. In the current study the strongest association was seen
with an SNP in <italic>IBSP,</italic> rs1054627, as was the case with two previous
studies <xref rid="pgen.1001372-Styrkarsdottir1" ref-type="bibr">[22]</xref>, <xref rid="pgen.1001372-Koller1" ref-type="bibr">[37]</xref>. Linkage disequilibrium between this SNP, and the
previously reported BMD-associated SNP rs1471403 in <italic>MEPE</italic>, is modest
(r<sup>2</sup> = 0.16). Whilst out study supports the
association of common variants in <italic>IBSP</italic> in particular with BMD,
further studies will be required to determine if more than one of these genes is
BMD-associated.</p><p>Recessive mutations of <italic>LTBP3</italic> have been identified as the cause of
dental agenesis in a consanguineous Pakistani family (OMIM 613097) <xref rid="pgen.1001372-Noor1" ref-type="bibr">[53]</xref>. Affected family
members had base of skull thickening, and elevated axial but not hip BMD.
<italic>LTBP3−/−</italic> mice develop axial osteosclerosis with
increased trabecular bone thickness, as well as craniosynostosis <xref rid="pgen.1001372-Dabovic1" ref-type="bibr">[54]</xref>. LTBP3 is
known to bind TGFβ1, -β2 and -β3, and may influence chondrocyte
maturation and enchondral ossification by effects on their bioavailability <xref rid="pgen.1001372-Dabovic1" ref-type="bibr">[54]</xref>.</p><p>Our study also confirms the previously reported association of another TGF pathway
gene, <italic>TGFBR3</italic>, encoded at chromosome 1p22, with BMD <xref rid="pgen.1001372-Xiong1" ref-type="bibr">[33]</xref> (<xref ref-type="supplementary-material" rid="pgen.1001372.s003">Figure S3E</xref>). In
that study, association was observed in four independent datasets, but overall the
findings did not achieve genome-wide significance at any individual SNP (most
significant SNP rs17131547,
P = 1.5×10<sup>−6</sup>). In our discovery set,
peak association was seen at this locus with SNP rs7550034 (TH
P = 1.5×10<sup>−4</sup>), which lies 154 kb
q-telomeric of rs17131547, but still within <italic>TGFBR3</italic> (rs17131547 was
not typed or imputed in our dataset) (<xref ref-type="supplementary-material" rid="pgen.1001372.s003">Figure S3E</xref>). This supports
<italic>TGFBR3</italic> as a true BMD-associated gene.</p><p>This study also demonstrated that <italic>SOX4</italic> polymorphisms are associated
with BMD variation. Both <italic>SOX4</italic> and <italic>SOX6</italic> are
cartilage-expressed transcription factors known to play essential roles in
chondrocyte differentiation and cartilage formation, and hence endochondral bone
formation. <italic>SOX6</italic> has previously been reported to be BMD-associated
at genome-wide significant levels <xref rid="pgen.1001372-Rivadeneira1" ref-type="bibr">[17]</xref>. Whilst
<italic>SOX4</italic>−/− mice develop severe cardiac abnormalities
and are non-viable, <italic>SOX4+/−</italic> mice have osteopaenia with
reduced bone formation but normal resorption rates, and diminished cortical and
trabecular bone volume <xref rid="pgen.1001372-NissenMeyer1" ref-type="bibr">[55]</xref>. Our data suggest that <italic>SOX4</italic>polymorphisms contribute to the variation in BMD in humans.</p><p>This study has a unique design amongst GWAS of BMD reported to date, using an
extreme-truncate ascertainment scheme, focusing on a specific skeletal site (TH),
and with recruitment of a narrow age- and gender-group (post-menopausal women age
55–85 years). Our goal in employing this scheme was to increase the study
power by reducing heterogeneity due to age-, gender- and skeletal site-specific
effects. Whilst osteoporotic fracture can occur at a wide range of skeletal sites,
hip fracture in postmenopausal women is the major cause of morbidity and mortality
due to osteoporosis. To date, with only one exception, all GWAS of BMD have studied
cohorts unselected for BMD <xref rid="pgen.1001372-Kung1" ref-type="bibr">[28]</xref>, and no study has restricted its participants to
postmenopausal women ascertained purely on the basis of hip BMD. Assuming
marker-disease-associated allele linkage disequilibrium of
r<sup>2</sup> = 0.9, for
alpha = 5×10<sup>−8</sup> our study has
80% power to detect variants contributing 0.3% of the additive genetic
variance of BMD. An equivalent-powered cohort study would require ∼16,000
unselected cases.</p><p>Considering the 26 known genes (or genomic areas) associated with BMD, P-values less
than <0.05 were seen in our discovery for 21 of the BMD-associated SNPs. Of the
26 known BMD genes, 16 would have been included in our replication study on the
basis of the strength of their BMD association in our discovery cohort, but were not
further genotyped as they were known already to be BMD-associated. Had these 16
genes replicated, 22 genes would have been identified in this single study,
demonstrating the power of the design of the current study.</p><p>A potential criticism of studies of highly selected cohorts, such as the
AOGC-discovery cohort, is that the associations identified may not be relevant in
the general population. However, the confirmation of our findings in replication
cohorts of women unselected for BMD confirms that our findings are of broad
relevance.</p><p>In summary, our study design therefore represents a highly efficient model for future
studies of quantitative traits and is one of the first reported studies using an
extreme truncate design in any disease. We have identified two new BMD loci at
genome-wide significance (<italic>GALNT3, RSPO3</italic>), with
<italic>GALNT3</italic> SNPs also associated with fracture. Strong evidence was
also demonstrated for four novel loci (<italic>CLCN7, IBSP</italic>, <italic>LTBP3,
SOX4</italic>). Further support was also provided that <italic>TGFBR3</italic>is a true BMD-associated locus. Our discovery cohort replicated 21 of 26 previously
identified BMD-associated loci. Our novel findings further advance our understanding
of the aetiopathogenesis of osteoporosis, and highlight new genes and pathways not
previously considered important in BMD variation and fracture risk in the general
population. Our study also provides strong support that the use of extreme truncate
selection is an efficient and powerful approach for the study of quantitative
traits.</p></sec><sec sec-type="materials|methods" id="s4"><title>Materials and Methods</title><sec id="s4a"><title>Ethics statement</title><p>All participants gave written, informed consent, and the study was approved by
the relevant research ethics authorities at each participating centre.</p></sec><sec id="s4b"><title>Subjects and phenotypes</title><p>The discovery sample population included 1128 Australian, 74 New Zealand and 753
British women, between 55–85 years of age, five or more years
postmenopausal, with either high BMD (age- and gender-adjusted BMD z-scores of
+1.5 to +4.0, n = 1055) or low BMD (age- and
gender-adjusted BMD z-scores of −4.0 to −1.5,
n = 900) (<xref ref-type="supplementary-material" rid="pgen.1001372.s004">Tables S1</xref> and <xref ref-type="supplementary-material" rid="pgen.1001372.s005">S2</xref>). BMD
z-scores were determined according to the Geelong Osteoporosis Study normative
range <xref rid="pgen.1001372-Henry2" ref-type="bibr">[19]</xref>. Low
BMD cases were excluded if they had secondary causes of osteoporosis, including
corticosteroid usage at doses equivalent to prednisolone ≥7.5 mg/day for
≥6 months, past or current anticonvulsant usage, previous strontium usage,
premature menopause (<45 years), alcohol excess (>28 units/week), chronic
renal or liver disease, Cushing's syndrome, hyperparathyroidism,
thyrotoxicosis, anorexia nervosa, malabsorption, coeliac disease, rheumatoid
arthritis, ankylosing spondylitis, inflammatory bowel disease, osteomalacia, and
neoplasia (cancer, other than skin cancer). Screening blood tests (including
creatinine (adjusted for weight), alkaline phosphatase, gamma-glutamyl
transferase, 25-hydroxyvitamin D and PTH) were checked in 776 cases, and no
differences were found between the high and low BMD groups. Therefore no further
screening tests were done of the remaining cases.</p><p>Fracture data were analysed comparing individuals who had never reported a
fracture after the age of 50 years, with individuals who had had a low or
non-high trauma (low trauma fracture = fracture from a
fall from standing height or less) osteoporotic fracture (excluding skull, nose,
digits, hand, foot, ankle, patella) after the age of 50 years. Vertebral, hip
and non-vertebral fractures were considered both independently and combined.</p><p>All participants were of self-reported white European ancestry.</p><p>DNA was obtained from peripheral venous blood from all cases except those
recruited from New Zealand, for whom DNA was obtained from salivary samples
using Oragene kits (DNA Genotek, Ontario, Canada). We have previously
demonstrated that DNA from these two sources have equivalent genotyping
characteristics <xref rid="pgen.1001372-Bahlo1" ref-type="bibr">[20]</xref>.</p><p>After quality control checks including assessment of cryptic relatedness,
ethnicity and genotyping quality, 900 individuals with low TH BMD and 1055
individuals with high TH BMD were available for analysis.</p><p>The replication cohort consisted of 8928 samples drawn from nine cohort studies,
outlined in <xref ref-type="supplementary-material" rid="pgen.1001372.s006">Tables S3</xref> and <xref ref-type="supplementary-material" rid="pgen.1001372.s007">S4</xref> (‘AOGC replication cohort’)
which were directly genotyped, These replication cases were adult women (age
20–95 years), unselected with regard to BMD, and who were not screened for
secondary causes of osteoporosis. Replication was also performed in silico in
11,970 adult women from the TwinsUK and Rotterdam, and deCODE Genetics GWASs
<xref rid="pgen.1001372-Richards1" ref-type="bibr">[21]</xref>,
<xref rid="pgen.1001372-Styrkarsdottir1" ref-type="bibr">[22]</xref>, <xref rid="pgen.1001372-Styrkarsdottir2" ref-type="bibr">[23]</xref>, in which
association data were available at LS and FN.</p><p>High and low BMD ascertainment was defined according to the TH score, because
this has better measurement precision than FN BMD <xref rid="pgen.1001372-Shepherd1" ref-type="bibr">[24]</xref>. However, neither TwinsUK
nor the Rotterdam Study had TH BMD on the majority of their datasets and
therefore were analysed using the FN measurement for which data were available
on the whole cohort. All replication findings at the hip are reported therefore
for FN BMD. TH and FN BMD are closely correlated (r = 0.882
in the AOGC dataset), with FN BMD one of the components of the TH BMD
measurement.</p></sec><sec id="s4c"><title>Genotyping</title><p>Genotyping of the discovery cohort (n = 2036) was performed
using Illumina Infinium II HumHap300 (n = 140), 370CNVDuo
(n = 4), 370CNVQuad (n = 1882) and
610Quad (n = 10) chips at the University of Queensland
Diamantina Institute, Brisbane, Australia. Genotype clustering was performed
using Illumina's BeadStudio software; all SNPs with quality scores <0.15
and all individuals with <98% genotyping success were excluded. 289499
SNPs were shared across all chip types. Cluster plots from the 500 most strongly
associated loci, were manually inspected and poorly clustering SNPs excluded
from analysis. Following imputation using the HapMap Phase 2 data, 2,543,887
SNPs were tested for association with TH and LS BMD (Manhattan plot of
association findings, <xref ref-type="supplementary-material" rid="pgen.1001372.s001">Figure S1</xref>). After data cleaning, minimal
evidence of inflation of test statistics was observed, with a genomic inflation
factor (λ) of 1.0282 (qq plot, <xref ref-type="supplementary-material" rid="pgen.1001372.s002">Figure S2</xref>).</p><p>A total of 124 SNPs were successfully genotyped in the AOGC replication cohort.
These replication study SNPs were selected from the findings of the discovery
cohort, either based on the strength of association (P-value) or following
analysis with GRAIL (n = 45) <xref rid="pgen.1001372-Raychaudhuri1" ref-type="bibr">[25]</xref>, using as seed data
all SNPs previously reported to be associated with BMD at GWAS significant
levels (results for all replication SNPs presented in <xref ref-type="supplementary-material" rid="pgen.1001372.s008">Table S5</xref>).
GRAIL is a bioinformatic program that assesses the strength of relationships
between genes in regions surrounding input SNPs (usually derived from genetic
association studies) and other SNPs or genes associated with the trait of
interest, by assessing their co-occurrence in PubMed abstracts. Where genes
surrounding input SNPs occur more frequently in abstracts with known associated
genes, these SNPs are more likely themselves also to be associated, and can thus
be prioritized for inclusion in replication studies.</p><p>For the replication study, genotyping was performed either by Applied Biosystems
OpenArray (n = 113) or Taqman technology
(n = 11) (Applied Biosystems, Foster City, CA, USA),
according to the manufacturer's protocol.</p></sec><sec id="s4d"><title>Statistical methods</title><p>Eleven individuals were removed because of abnormal X-chromosome homozygosity
(X-chromosome homozygosity either <−0.14, or >+0.14). Outliers
with regard to autosomal heterozygosity (either <0.34225 or >0.357,
n = 40) and missingness (>3%,
n = 4) were removed. Using an IBS/IBD analysis in PLINK to
detect cryptic relatedness, one individual from 35 pairs of individuals with
pi-hat >0.12 (equivalent to being 3<sup>rd</sup> degree relatives or closer)
were removed. SNPs with minor allele frequency <1%
(n = 561), and those not in Hardy-Weinberg equilibrium
(P<10<sup>−7</sup>, n = 170) were then
removed, leaving 288,768 SNPs in total. Nine replication SNPs were removed
because of excess missingness (>10%) or because they failed tests of
Hardy-Weinberg equilibrium (P<0.001).</p><p>To detect and correct for population stratification EIGENSTRAT software was used.
We first excluded the 24 regions of long range LD including the MHC identified
in Price et al. before running the principal components analysis, as suggested
by the authors <xref rid="pgen.1001372-Price1" ref-type="bibr">[26]</xref>. Sixteen individuals were removed as ethnic outliers,
leaving 1955 individuals in the final discovery dataset.</p><p>Imputation analyses were carried out using Markov Chain Haplotyping software
(MaCH; <ext-link ext-link-type="uri" xlink:href="http://www.sph.umich.edu/csg/abecasis/MACH/">http://www.sph.umich.edu/csg/abecasis/MACH/</ext-link>) using phased data
from CEU individuals from release 22 of the HapMap project as the reference set
of haplotypes. We only analyzed SNPs surrounding disease-associated SNPs that
were either genotyped or could be imputed with relatively high confidence
(R<sup>2</sup>≥0.3). For TH measurements, a case-control association
analysis of imputed SNPs was performed assuming an underlying additive model and
including four EIGENSTRAT eigenvectors as covariates, using the software package
MACH2DAT <xref rid="pgen.1001372-Li1" ref-type="bibr">[27]</xref>which accounts for uncertainty in prediction of the imputed data by weighting
genotypes by their posterior probabilities. For FN and LS BMD analyses,
Z-transformed residual BMD scores (in g/cm<sup>2</sup>) were generated for the
entire AOGC cohort after adjusting for the covariates age, age<sup>2</sup>, and
weight, and for centre of BMD measurement. Because the regression coefficient
for BMD on genotype would be biased by selection for extremes, we adopted the
approach detailed in Kung et al (2009) <xref rid="pgen.1001372-Kung1" ref-type="bibr">[28]</xref>. Specifically, the regression
coefficient of genotype on BMD was estimated, and subsequently transformed to
the regression coefficient of BMD on genotype through knowledge of the
population variance of the phenotype and the allele frequencies. For fracture
data, analysis was by logistic regression. Only SNPs achieving GWAS significance
were tested for fracture association. The SNPs used for replication from the
Rotterdam Study were analyzed using MACH2QTL implemented in GRIMP <xref rid="pgen.1001372-Estrada1" ref-type="bibr">[29]</xref>. Data from
the discovery and replication cohorts were combined using the inverse variance
approach as implemented in the program METAL <xref rid="pgen.1001372-Willer1" ref-type="bibr">[30]</xref>.</p><p>SNPs associated with BMD were also tested for association with fracture in the
AOGC discovery and replication cohorts (hip, vertebral, nonvertebral, and all
low trauma fractures, age ≥50 years, as defined above), by logistic
regression.</p><p>Study power was calculated using the ‘Genetic Power Calculator’ <xref rid="pgen.1001372-Purcell1" ref-type="bibr">[31]</xref>.</p></sec><sec id="s4e"><title>Mouse BMD analysis</title><p>All animal studies were approved by the MRC Harwell Unit Ethical Review Committee
and are licensed under the Animal (Scientific Procedures) Act 1986, issued by
the UK Government Home Office Department. Dual-energy X-ray absorptiometry
(DEXA) was performed using a Lunar Piximus densitometer (GE Medical Systems) and
analysed using the Piximus software.</p></sec><sec id="s4f"><title>Data availability</title><p>Data related to this study will be available to research projects approved by a
Data Access Committee including representatives of the University of Queensland
Research Ethics Committee. For enquiries regarding access please contact the
corresponding author, MAB (<email>matt.brown@uq.edu.au</email>).</p></sec></sec><sec sec-type="supplementary-material" id="s5"><title>Supporting Information</title><supplementary-material content-type="local-data" id="pgen.1001372.s001"><label>Figure S1</label><caption><p>Manhattan plot of discovery genome-wide association study findings for BMD at
total hip. P = 10<sup>−5</sup> is indicated by a
blue horizontal line.</p><p>(0.51 MB TIF)</p></caption><media xlink:href="pgen.1001372.s001.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s002"><label>Figure S2</label><caption><p>Genomic control findings. The genomic inflation factor (λ) when reported
as the median χ<sup>2</sup> was 1.0282.</p><p>(0.36 MB TIF)</p></caption><media xlink:href="pgen.1001372.s002.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s003"><label>Figure S3</label><caption><p>SNP association plots for OP-associated regions. Discovery cohort association
significance level is plotted against the left hand y-axis as
-log10(P-values). Genetic coordinates are as per NCBI build 36.1. Filled
circles represent genotyped SNPs, and outlined diamonds represent imputed
SNPs. The recombination rate (cM/Mb as per HapMap data) is indicated by the
purple dotted line and right hand y-axis. Genes and ESTs are indicated with
their approximate sizes and direction of translation. (A) Chromosome 16p13 -
<italic>CLCN7</italic> region. SNP association plot of findings from TH
case-control analysis of AOGC discovery set for a 100 kb region (1,420 kb to
1,520 kb) of chromosome 16. LD is indicated by colour scale in relationship
to marker rs13336428. (B) Chromosome 4q22 - <italic>IBSP</italic> region.
SNP association plot of findings from TH case-control analysis of AOGC
discovery set for a 500 kb region (88,700 kb to 89,200 kb) of chromosome 4.
LD is indicated by colour scale in relationship to marker rs1054627. (C)
Chromosome 11p13 - <italic>LTBP3</italic> region. SNP association plot of
findings from TH case-control analysis of AOGC discovery set for a 300 kb
region (64,950 kb to 65,250 kb) of chromosome 11. LD is indicated by colour
scale in relationship to marker rs1152620. (D) Chromosome 6p22 -
<italic>SOX4</italic> region. SNP association plot of findings from TH
case-control analysis of AOGC discovery set for a 2 Mb region (20,500 kb to
22,500 kb) of chromosome 6. LD is indicated by colour scale in relationship
to marker rs9466056. (E) Chromosome 1p22 - <italic>TGFBR3</italic> region.
SNP association plot of findings from TH case-control analysis of AOGC
discovery set for a 1 Mb region (91,800 kb to 92,800 kb) of chromosome 1. LD
is indicated by colour scale in relationship to marker rs7550034.</p><p>(5.13 MB TIF)</p></caption><media xlink:href="pgen.1001372.s003.tif"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s004"><label>Table S1</label><caption><p>Case numbers for the discovery cohort, with BMD affection status and fracture
history.</p><p>(0.05 MB DOC)</p></caption><media xlink:href="pgen.1001372.s004.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s005"><label>Table S2</label><caption><p>Descriptive statistics for discovery cohort.</p><p>(0.06 MB DOC)</p></caption><media xlink:href="pgen.1001372.s005.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s006"><label>Table S3</label><caption><p>Replication cohort details.</p><p>(0.04 MB DOC)</p></caption><media xlink:href="pgen.1001372.s006.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s007"><label>Table S4</label><caption><p>Replication cohort fracture data.</p><p>(0.04 MB DOC)</p></caption><media xlink:href="pgen.1001372.s007.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s008"><label>Table S5</label><caption><p>Replication study SNPs, beta coefficients and P-values for analysis of TH, FN
and LS. The regression coefficient in the case-control analysis of TH in the
discovery set shows the expected increase in the log odds ratio of low BMD
per addition of allele A2. The regression coefficients in the TH, FN and LS
analyses refer to the expected increase in standardized BMD per addition of
allele A2 in the discovery set.</p><p>(0.22 MB DOC)</p></caption><media xlink:href="pgen.1001372.s008.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material><supplementary-material content-type="local-data" id="pgen.1001372.s009"><label>Table S6</label><caption><p>Association findings in AOGC discovery set for markers achieving genome-wide
significant association with BMD in previous studies. The regression
coefficient in the TH analysis shows the expected increase in the log odds
ratio of low BMD per addition of allele A2. The regression coefficients in
the FN and LS analyses refer to the expected increase in standardized BMD
per addition of allele A2.</p><p>(0.12 MB DOC)</p></caption><media xlink:href="pgen.1001372.s009.doc"><caption><p>Click here for additional data file.</p></caption></media></supplementary-material></sec></body><back><ack><p>We would like to thank all participants who provided the DNA and clinical information
necessary for this study. We would like to gratefully acknowledge the contributions
of Prof. Gunnar Sigurdsson and Dr. Unnur Thorsteinsdottir (Iceland) for their
valuable contribution to the study. We thank Pascal Arp, Mila Jhamai, Dr Michael
Moorhouse, Marijn Verkerk, and Sander Bervoets for their help in creating the
Rotterdam GWAS database. The authors are grateful to the Rotterdam study
participants, the staff from the Rotterdam Study, and the participating general
practioners and pharmacists. We thank Barbara Mason and Amanda Horne (Auckland) for
patient recruitment; Judith Finigan (Sheffield) for laboratory support and database
support; Selina Simpson (Sheffield) for DNA handling; Fatma Gossiel (Sheffield) for
DNA handling; Alison Steward and Lana Gibson (Aberdeen) for patient recruitment;
Katherine Kolk (Geelong); Janelle Rampellini (Perth) for patient recruitment; Jemma
Christie (Melbourne) for patient recruitment; Helen Steane (Hobart) for patient
recruitment; Denia Mang and Ruth Toppler for DNA extraction, DNA handling, and
database support (Dubbo/Sydney); Kate Lowings (Brisbane) for patient recruitment;
and Marieke Brugmans and Leanne Brookes (Brisbane) for DNA preparation and
genotyping.</p></ack><fn-group><fn fn-type="COI-statement"><p>The authors have declared that no competing interests exist.</p></fn><fn fn-type="financial-disclosure"><p>This study was funded by the National Health and Medical Research Council
(Australia) (grant reference 511132). Funding was also received from the
Australian Cancer Research Foundation and Rebecca Cooper Foundation (Australia).
MAB is funded by a National Health and Medical Research Council (Australia)
Principal Research Fellowship and ELD is funded by a National Health and Medical
Research Council (Australia) Career Development Award (569807). DME is supported
by a Medical Research Council New Investigator Award (MRC G0800582). JPK is
funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and
life course epidemiology (WT083431MA). IRR is supported by the Health Research
Council of New Zealand. The OPUS study was supported by Sanofi-Aventis, Eli
Lilly, Novartis, Pfizer, Proctor and Gamble Pharmaceuticals, and Roche. CE, RDC,
SDMB, RVT, and MAB are supported by a Medical Research Council (UK) grant (MRC
G0600702). The generation and management of GWAS genotype data for the Rotterdam
Study were supported by the Netherlands Organisation of Scientific Research NWO
Investments (nr. 175.010.2005.011, 911-03-012); the Research Institute for
Diseases in the Elderly (014-93-015; RIDE2); the Netherlands Genomics Initiative
(NGI)/Netherlands Organisation for Scientific Research (NWO) project nr.
050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus
University, Rotterdam, Netherlands Organization for the Health Research and
Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE),
the Ministry of Education, Culture, and Science, the Ministry for Health,
Welfare and Sports, the European Commission (DG XII), and the Municipality of
Rotterdam. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis
Abuseiris, and Rob de Graaf, as well as their institutions the Erasmus Computing
Grid, Rotterdam, The Netherlands, and especially the national German MediGRID
and Services@MediGRID part of the German D-Grid, both funded by the
German Bundesministerium fuer Forschung und Technology under grants #01 AK 803
A–H and # 01 IG 07015 G for access to their grid resources. The Sydney
Twin Study and Tasmanian Older Adult Cohort were supported by the National
Health and Medical Research Council, Australia. The Dubbo Osteoporosis
Epidemiology Study was supported by the Australian National Health and Medical
Research Council, MBF Living Well foundation, the Ernst Heine Family Foundation,
and from untied educational grants from Amgen, Eli Lilly International,
GE-Lunar, Merck Australia, Novartis, Sanofi-Aventis Australia, and Servier. The
Calcium Intake Fracture Outcome Study was supported by Healthway Health
Promotion Foundation of Western Australia, the Australasian Menopause Society,
and the National Health and Medical Research Council. The Hertfordshire Cohort
Study was supported by grants from the Medical research Council UK and Arthritis
Research UK. JBR has received support from the Canadian Institutes of Health
Research, Canadian Foundation for Innovation, Fonds de la Recherche en Sante
Quebec, Lady Davis Institute, and Ministere du Développement
économique, innovation et exportation du Quebec. The Twins UK study is
supported by The Wellcome Trust, Arthritis Research UK, the Chronic Disease
Research Foundation, the Canadian Institutes of Health Research, the European
Society for Clinical and Economic aspects of Osteoporosis, the European Union
GenomEUtwin Project, and the National Institute for Health Research. The Geelong
Osteoporosis Study was funded by grants from the Victorian Health Promotion
Foundation and the Geelong Region Medical Research Foundation and by the
National Health and Medical Research Council, Australia (project grant 628582).
The Oxford Osteoporosis Study was funded by Action Research UK. The ENU
mutagenesis program is supported by the Medical research council project grant
G0600702. The funders had no role in study design, data collection or analysis,
decision to publish, or preparation of the manuscript.</p></fn></fn-group><ref-list><title>References</title><ref id="pgen.1001372-US1"><label>1</label><element-citation publication-type="other"><collab>US Department of Health and Human Services</collab><year>2004</year><article-title>Bone health and Osteoporosis: a report of the surgeon
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