title: Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.
abstract: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.
authors.affiliation: Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.|Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.
authors.forename: Hou-Feng
authors.initials: HF
authors.lastname: Zheng
authors.affiliation: Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.|Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Forgetta
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.|Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA.
authors.forename: Yi-Hsiang
authors.initials: YH
authors.lastname: Hsu
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.|Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA.|Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Karol
authors.initials: K
authors.lastname: Estrada
authors.affiliation: Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Alberto
authors.initials: A
authors.lastname: Rosello-Diez
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Leo
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA.|Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA.
authors.forename: Chitra L
authors.initials: CL
authors.lastname: Dahia
authors.affiliation: Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA.
authors.forename: Kyung Hyun
authors.initials: KH
authors.lastname: Park-Min
authors.affiliation: School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Tobias
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Kooperberg
authors.affiliation: Department of Research, 23andMe, Mountain View, California 94041, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Kleinman
authors.affiliation: Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Styrkarsdottir
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
authors.forename: Ching-Ti
authors.initials: CT
authors.lastname: Liu
authors.affiliation: Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Uggla
authors.affiliation: California Pacific Medical Center Research Institute, San Francisco, California 94158, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Evans
authors.affiliation: Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.|Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Carrie M
authors.initials: CM
authors.lastname: Nielson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Klaudia
authors.initials: K
authors.lastname: Walter
authors.affiliation: Departments of Pharmacology and Clinical Neurosciences, Umeå University, Umeå S-901 87, Sweden.|Department of Public Health and Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Pettersson-Kymmer
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: McCarthy
authors.affiliation: Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.|Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.
authors.forename: Joel
authors.initials: J
authors.lastname: Eriksson
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Kwan
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: Mila
authors.initials: M
authors.lastname: Jhamai
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: Katerina
authors.initials: K
authors.lastname: Trajanoska
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Yasin
authors.initials: Y
authors.lastname: Memari
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Josine
authors.initials: J
authors.lastname: Min
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Petr
authors.initials: P
authors.lastname: Danecek
authors.affiliation: Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.|Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Beth
authors.initials: B
authors.lastname: Wilmot
authors.affiliation: Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.|Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Wen-Chi
authors.initials: WC
authors.lastname: Chou
authors.affiliation: Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Mokry
authors.affiliation: Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK.|Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Alireza
authors.initials: A
authors.lastname: Moayyeri
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.|Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Melina
authors.initials: M
authors.lastname: Claussnitzer
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.
authors.forename: Chia-Ho
authors.initials: CH
authors.lastname: Cheng
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.|Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.
authors.forename: Warren
authors.initials: W
authors.lastname: Cheung
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
authors.forename: Carolina
authors.initials: C
authors.lastname: Medina-Gómez
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Ge
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.
authors.forename: Shu-Huang
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA.
authors.forename: Kwangbom
authors.initials: K
authors.lastname: Choi
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
authors.forename: Ling
authors.initials: L
authors.lastname: Oei
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal H3G 1Y6, Canada.
authors.forename: James
authors.initials: J
authors.lastname: Fraser
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Kraaij
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA.|Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Hibbs
authors.affiliation: Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK.
authors.forename: Celia L
authors.initials: CL
authors.lastname: Gregson
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal H3G 1Y6, Canada.
authors.forename: Denis
authors.initials: D
authors.lastname: Paquette
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Radiation Sciences, Umeå University, Umeå S-901 87, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Wibom
authors.affiliation: Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.|Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tranah
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Mhairi
authors.initials: M
authors.lastname: Marshall
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Brooke B
authors.initials: BB
authors.lastname: Gardiner
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Katie
authors.initials: K
authors.lastname: Cremin
authors.affiliation: School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Auer
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Hsu
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Sue
authors.initials: S
authors.lastname: Ring
authors.affiliation: Department of Research, 23andMe, Mountain View, California 94041, USA.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Tung
authors.affiliation: Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland.
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: Anke W
authors.initials: AW
authors.lastname: Enneman
authors.affiliation: Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands.
authors.forename: Natasja M
authors.initials: NM
authors.lastname: van Schoor
authors.affiliation: Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands.
authors.forename: Lisette C P G M
authors.initials: LC
authors.lastname: de Groot
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands.
authors.forename: Nathalie
authors.initials: N
authors.lastname: van der Velde
authors.affiliation: Department of Radiation Sciences, Umeå University, Umeå S-901 87, Sweden.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Melin
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Kemp
authors.affiliation: Nordic Bioscience, Herlev 2730, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Christiansen
authors.affiliation: Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK.
authors.forename: Adrian
authors.initials: A
authors.lastname: Sayers
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France.|Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Calderari
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: van Rooij
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Carlson
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Peters
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal H3G 1Y6, Canada.
authors.forename: Soizik
authors.initials: S
authors.lastname: Berlivet
authors.affiliation: Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montréal H3G 1Y6, Canada.
authors.forename: Josée
authors.initials: J
authors.lastname: Dostie
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
authors.forename: Andre G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Williams
authors.affiliation: Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Farber
authors.affiliation: Department of Genetics, University of Barcelona, Barcelona 08028, Spain.|U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain.|Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Grinberg
authors.affiliation: Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA.
authors.forename: Andrea Z
authors.initials: AZ
authors.lastname: LaCroix
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Haessler
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Chasman
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors.forename: Franco
authors.initials: F
authors.lastname: Giulianini
authors.affiliation: Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Rose
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.|Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Ridker
authors.affiliation: Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia.|School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia.|St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Eisman
authors.affiliation: Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia.|St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia.
authors.forename: Tuan V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia.|St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia.
authors.forename: Jacqueline R
authors.initials: JR
authors.lastname: Center
authors.affiliation: Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.|Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain.|Department of Internal Medicine, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona 08193, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Nogues
authors.affiliation: Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mèdiques, Barcelona 08003, Spain.|Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Garcia-Giralt
authors.affiliation: Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lenore L
authors.initials: LL
authors.lastname: Launer
authors.affiliation: Icelandic Heart Association, Kopavogur IS-201, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland.
authors.forename: Vilmunder
authors.initials: V
authors.lastname: Gudnason
authors.affiliation: Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.
authors.forename: Dan
authors.initials: D
authors.lastname: Mellström
authors.affiliation: Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Vandenput
authors.affiliation: Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands.
authors.forename: Najaf
authors.initials: N
authors.lastname: Amin
authors.affiliation: Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: Department of Orthopaedics, Skåne University Hospital Malmö 205 02, Sweden.
authors.forename: Magnus K
authors.initials: MK
authors.lastname: Karlsson
authors.affiliation: Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden.
authors.forename: Östen
authors.initials: Ö
authors.lastname: Ljunggren
authors.affiliation: Department of Surgical and Perioperative Sciences, Umeå Unviersity, Umeå 901 85, Sweden.
authors.forename: Olle
authors.initials: O
authors.lastname: Svensson
authors.affiliation: Department of Public Health and Clinical Medicine, Umeå University, Umeå SE-901 87, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Hallmans
authors.affiliation: Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec City G1V 0A6, Canada.|Axe Santé des Populations et Pratiques Optimales en Santé, Centre de recherche du CHU de Québec, Québec City G1V 4G2, Canada.
authors.forename: François
authors.initials: F
authors.lastname: Rousseau
authors.affiliation: Axe Santé des Populations et Pratiques Optimales en Santé, Centre de recherche du CHU de Québec, Québec City G1V 4G2, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Giroux
authors.affiliation: Axe Santé des Populations et Pratiques Optimales en Santé, Centre de recherche du CHU de Québec, Québec City G1V 4G2, Canada.
authors.forename: Johanne
authors.initials: J
authors.lastname: Bussière
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: Pascal P
authors.initials: PP
authors.lastname: Arp
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: Fjorda
authors.initials: F
authors.lastname: Koromani
authors.affiliation: Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia.|Department of Medicine, University of Western Australia, Perth 6009, Australia.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Prince
authors.affiliation: Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia.|Department of Medicine, University of Western Australia, Perth 6009, Australia.
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Lewis
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark.
authors.forename: Bente L
authors.initials: BL
authors.lastname: Langdahl
authors.affiliation: Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark.
authors.forename: A Pernille
authors.initials: AP
authors.lastname: Hermann
authors.affiliation: Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark.
authors.forename: Jens-Erik B
authors.initials: JE
authors.lastname: Jensen
authors.affiliation: Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kaptoge
authors.affiliation: Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK.
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.affiliation: Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.|Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Reeve
authors.affiliation: Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta.
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Formosa
authors.affiliation: Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta.
authors.forename: Angela
authors.initials: A
authors.lastname: Xuereb-Anastasi
authors.affiliation: Department of Orthopaedics, Skåne University Hospital Malmö 205 02, Sweden.|Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University, 205 02, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Åkesson
authors.affiliation: Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University, 205 02, Sweden.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: McGuigan
authors.affiliation: Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmö, Lund University, 205 02, Sweden.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Garg
authors.affiliation: Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain.|Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Olmos
authors.affiliation: Department of Legal Medicine, University of Cantabria, Santander 39011, Spain.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Zarrabeitia
authors.affiliation: Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain.|Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Riancho
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.affiliation: Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Nerea
authors.initials: N
authors.lastname: Alonso
authors.affiliation: Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Medicine and Physiology, McGill University, Montréal H4A 3J1, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.|Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.
authors.forename: Tomi
authors.initials: T
authors.lastname: Pastinen
authors.affiliation: McGill University and Genome Quebec Innovation Centre, Montréal H3A 0G1, Canada.|Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.
authors.forename: Elin
authors.initials: E
authors.lastname: Grundberg
authors.affiliation: Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France.|Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Gauguier
authors.affiliation: Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA.|Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Orwoll
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.|Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Karasik
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: George
authors.initials: G
authors.lastname: Davey-Smith
authors.affiliation: Icelandic Heart Association, Kopavogur IS-201, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland.
authors.forename: Albert V
authors.initials: AV
authors.lastname: Smith
authors.affiliation: Icelandic Heart Association, Kopavogur IS-201, Iceland.
authors.forename: Kristin
authors.initials: K
authors.lastname: Siggeirsdottir
authors.affiliation: Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Tamara B
authors.initials: TB
authors.lastname: Harris
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: M Carola
authors.initials: MC
authors.lastname: Zillikens
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.
authors.forename: Joyce B J
authors.initials: JB
authors.lastname: van Meurs
authors.affiliation: Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Maurano
authors.affiliation: MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Timpson
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Nicole
authors.initials: N
authors.lastname: Soranzo
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Durbin
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.|Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia.|School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia.
authors.forename: Scott G
authors.initials: SG
authors.lastname: Wilson
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece.|Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA.
authors.forename: Evangelia E
authors.initials: EE
authors.lastname: Ntzani
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland.|deCODE Genetics, Reykjavik IS-101, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: Department of Research, 23andMe, Mountain View, California 94041, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: Tim
authors.initials: T
authors.lastname: Spector
authors.affiliation: Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.|Framingham Heart Study, Framingham, Massachusetts 01702, USA.
authors.forename: L Adrienne
authors.initials: LA
authors.lastname: Cupples
authors.affiliation: Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
authors.affiliation: Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.|Department of Human Genetics, McGill University, Montréal H3A 1B1, Canada.|Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montréal H3A 1A2, Canada.|Department of Oncology, Gerald Bronfman Centre, McGill University, Montréal H2W 1S6, Canada.
authors.forename: Celia M T
authors.initials: CM
authors.lastname: Greenwood
authors.affiliation: Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Jackson
authors.affiliation: Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Rowe
authors.affiliation: The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Loomis
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.|MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Evans
authors.affiliation: Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Ackert-Bicknell
authors.affiliation: Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Joyner
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia.|Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Duncan
authors.affiliation: Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA.|Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.|Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA.|Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Kiel
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands.|Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands.
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivadeneira
authors.affiliation: Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montréal H3A 1A2, Canada.|Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montréal H3T 1E2, Canada.|Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK.
authors.forename: J Brent
authors.initials: JB
authors.lastname: Richards
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics*; D001842:Bone and Bones / Q000378:metabolism; D004195:Disease Models, Animal; D005060:Europe / Q000208:ethnology; D059472:Exome / Q000235:genetics; D005260:Female; D050723:Fractures, Bone / Q000235:genetics*; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics
chemical_list: C513076:EN1 protein, human; C080330:En1 protein, mouse; D018398:Homeodomain Proteins; C417262:WNT16 protein, human; D051153:Wnt Proteins