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Osteoporosis: HELP
Articles by Emma L. Duncan
Based on 13 articles published since 2010
(Why 13 articles?)

Between 2010 and 2020, E. Duncan wrote the following 13 articles about Osteoporosis.
+ Citations + Abstracts
1 Review The genetics of osteoporosis. 2015

Clark, Graeme R / Duncan, Emma L. ·Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK. · Human Genetics Group, The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba QLD 4102, Australia Mayne Medical School, School of Medicine, Faculty of Medicine and Biomedical Sciences, The University of Queensland, 288 Herston Road, Herston, QLD, 4006, Australia Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Butterfield Road, Herston QLD 4029, Australia emma.duncan@uq.edu.au. ·Br Med Bull · Pubmed #25634850.

ABSTRACT: INTRODUCTION: Osteoporosis is the commonest metabolic bone disease worldwide. The clinical hallmark of osteoporosis is low trauma fracture, with the most devastating being hip fracture, resulting in significant effects on both morbidity and mortality. SOURCES OF DATA: Data for this review have been gathered from the published literature and from a range of web resources. AREAS OF AGREEMENT: Genome-wide association studies in the field of osteoporosis have led to the identification of a number of loci associated with both bone mineral density and fracture risk and further increased our understanding of disease. AREAS OF CONTROVERSY: The early strategies for mapping osteoporosis disease genes reported only isolated associations, with replication in independent cohorts proving difficult. Neither candidate gene or linkage studies showed association at genome-wide level of significance. GROWING POINTS: The advent of massive parallel sequencing technologies has proved extremely successful in mapping monogenic diseases and thus leading to the utilization of this new technology in complex disease genetics. AREAS TIMELY FOR DEVELOPING RESEARCH: The identification of novel genes and pathways will potentially lead to the identification of novel therapeutic options for patients with osteoporosis.

2 Review Next-generation sequencing: a frameshift in skeletal dysplasia gene discovery. 2014

Lazarus, S / Zankl, A / Duncan, E L. ·University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, QLD, 4029, Australia. ·Osteoporos Int · Pubmed #23903953.

ABSTRACT: In the last decade, huge breakthroughs in genetics-driven by new technology and different statistical approaches-have resulted in a plethora of new disease genes identified for both common and rare diseases. Massive parallel sequencing, commonly known as next-generation sequencing, is the latest advance in genetics, and has already facilitated the discovery of the molecular cause of many monogenic disorders. This article describes this new technology and reviews how this approach has been used successfully in patients with skeletal dysplasias. Moreover, this article illustrates how the study of rare diseases can inform understanding and therapeutic developments for common diseases such as osteoporosis.

3 Review Clinical review 2: Genetic determinants of bone density and fracture risk--state of the art and future directions. 2010

Duncan, Emma L / Brown, Matthew A. ·University of Queensland Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Queensland 4102, Australia. e.duncan@uq.edu.au ·J Clin Endocrinol Metab · Pubmed #20375209.

ABSTRACT: CONTEXT: Osteoporosis is a common, highly heritable condition that causes substantial morbidity and mortality, the etiopathogenesis of which is poorly understood. Genetic studies are making increasingly rapid progress in identifying the genes involved. EVIDENCE ACQUISITION AND SYNTHESIS: In this review, we will summarize the current understanding of the genetics of osteoporosis based on publications from PubMed from the year 1987 onward. CONCLUSIONS: Most genes involved in osteoporosis identified to date encode components of known pathways involved in bone synthesis or resorption, but as the field progresses, new pathways are being identified. Only a small proportion of the total genetic variation involved in osteoporosis has been identified, and new approaches will be required to identify most of the remaining genes.

4 Review Mapping genes for osteoporosis--old dogs and new tricks. 2010

Duncan, Emma L / Brown, Matthew A. ·Diamantina Institute of Cancer, Immunology and Metabolic Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, QLD 4102, Australia. ·Bone · Pubmed #20060943.

ABSTRACT: In stark contrast to its horticultural origins, modern genetics is an extremely technology-driven field. Almost all the major advances in the field over the past 20 years have followed technological developments that have permitted change in study designs. The development of PCR in the 1980s led to RFLP mapping of monogenic diseases. The development of fluorescent-tagged genotyping methods led to linkage mapping approaches for common diseases that dominated the 1990s. The development of microarray SNP genotyping has led to the genome-wide association study era of the new millennium. And now the development of next-generation sequencing technologies is about to open up a new era of gene-mapping, enabling many potential new study designs. This review aims to present the strengths and weaknesses of the current approaches, and present some new ideas about gene-mapping approaches that are likely to advance our knowledge of the genes involved in heritable bone traits such as bone mineral density (BMD) and fracture.

5 Article Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density. 2018

Alonso, Nerea / Estrada, Karol / Albagha, Omar M E / Herrera, Lizbeth / Reppe, Sjur / Olstad, Ole K / Gautvik, Kaare M / Ryan, Niamh M / Evans, Kathryn L / Nielson, Carrie M / Hsu, Yi-Hsiang / Kiel, Douglas P / Markozannes, George / Ntzani, Evangelia E / Evangelou, Evangelos / Feenstra, Bjarke / Liu, Xueping / Melbye, Mads / Masi, Laura / Brandi, Maria Luisa / Riches, Philip / Daroszewska, Anna / Olmos, José Manuel / Valero, Carmen / Castillo, Jesús / Riancho, José A / Husted, Lise B / Langdahl, Bente L / Brown, Matthew A / Duncan, Emma L / Kaptoge, Stephen / Khaw, Kay-Tee / Usategui-Martín, Ricardo / Del Pino-Montes, Javier / González-Sarmiento, Rogelio / Lewis, Joshua R / Prince, Richard L / D'Amelio, Patrizia / García-Giralt, Natalia / Nogués, Xavier / Mencej-Bedrac, Simona / Marc, Janja / Wolstein, Orit / Eisman, John A / Oei, Ling / Medina-Gómez, Carolina / Schraut, Katharina E / Navarro, Pau / Wilson, James F / Davies, Gail / Starr, John / Deary, Ian / Tanaka, Toshiko / Ferrucci, Luigi / Gianfrancesco, Fernando / Gennari, Luigi / Lucas, Gavin / Elosua, Roberto / Uitterlinden, André G / Rivadeneira, Fernando / Ralston, Stuart H. ·Rheumatology and Bone Disease Unit, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. · Departments of Internal Medicine and Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands. · Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar. · Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway. · Department of Clinical Biochemistry, Lovisenberg Diakonale Hospital, Oslo, Norway. · Department of Molecular Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. · Centre for Genomic and Experimental Medicine, IGMM, University of Edinburgh, Edinburgh, UK. · Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. · Department of Public Health and Preventive Medicine, Oregon Health and Science University, Portland, Oregon, USA. · Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. · BROAD Institute of MIT and Harvard, Cambridge, Massachusetts, USA. · Musculoskeletal Research Center, Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece. · Centre for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Rhode Island, USA. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark. · Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. · Department of Medicine, Stanford School of Medicine, Stanford, California, USA. · Department of Surgery and Translational Medicine, University of Florence, Florence, Italy. · Institute of Ageing and Chronic Disease, The MRC-Arthritis Research UK Centre for Integrated Research into Musculoskeletal Ageing, University of Liverpool, Liverpool, UK. · Department of Internal Medicine, Hospital UM Valdecilla, University of Cantabria, IDIVAL, RETICEF, Santander, Spain. · Department of Endocrinology and Internal Medicine THG, Aarhus University Hospital, Aarhus, Denmark. · Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia. · Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia. · Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia. · Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Department of Public Health and Primary Care, School of Medicine, University of Cambridge, Cambridge, UK. · Molecular Medicine Unit, Department of Medicine and Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca, University of Salamanca - CSIC, Salamanca, Spain. · School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia. · Centre for Kidney Research, School of Public Health, University of Sydney, Sydney, New South Wales, Australia. · School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, Australia. · Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia. · Gerontology and Bone Metabolic Diseases Unit, Department of Medical Science, University of Torino, Torino, Italy. · Department of Internal Medicine, Hospital del Mar-IMIM, RETICEF, Universitat Autonoma de Barcelona, Barcelona, Spain. · Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia. · Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK. · Edinburgh/British Heart Foundation Centre for Cardiovascular Science, QMRI, University of Edinburgh, Edinburgh, UK. · MRC Human Genetics Unit, MRC, IGMM, University of Edinburgh, Edinburgh, UK. · Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, Maryland, USA. · Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", National Research Council of Italy, Naples, Italy. · Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy. · Grup de Recerca en Genètica i Epidemiologia Cardiovascular, IMIM, Barcelona, Spain. ·Ann Rheum Dis · Pubmed #29170203.

ABSTRACT: OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10 CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

6 Article Identification of IDUA and WNT16 Phosphorylation-Related Non-Synonymous Polymorphisms for Bone Mineral Density in Meta-Analyses of Genome-Wide Association Studies. 2016

Niu, Tianhua / Liu, Ning / Yu, Xun / Zhao, Ming / Choi, Hyung Jin / Leo, Paul J / Brown, Matthew A / Zhang, Lei / Pei, Yu-Fang / Shen, Hui / He, Hao / Fu, Xiaoying / Lu, Shan / Chen, Xiang-Ding / Tan, Li-Jun / Yang, Tie-Lin / Guo, Yan / Cho, Nam H / Shen, Jie / Guo, Yan-Fang / Nicholson, Geoffrey C / Prince, Richard L / Eisman, John A / Jones, Graeme / Sambrook, Philip N / Tian, Qing / Zhu, Xue-Zhen / Papasian, Christopher J / Duncan, Emma L / Uitterlinden, André G / Shin, Chan Soo / Xiang, Shuanglin / Deng, Hong-Wen. ·Department of Biostatistics and Bioinformation, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, USA. · College of Life Science, Hunan Normal University, Changsha, P.R. China. · Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Korea. · Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea. · University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia. · Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, P.R. China. · School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, P.R. China. · Department of Preventive Medicine, Ajou University School of Medicine, Youngtong-Gu, Korea. · Third Affiliated Hospital of Southern Medical University, Guangzhou, P.R. China. · School of Medicine, The University of Queensland, Toowoomba, Australia. · School of Medicine and Pharmacology, University of Western Australia, Perth, Australia. · Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Perth, Australia. · Garvan Institute of Medical Research, University of New South Wales, Sydney, Australia. · Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia. · Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia. · Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA. · Department of Endocrinology, Royal Brisbane and Women's Hospital, Brisbane, Australia. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands. · Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, The Netherlands. ·J Bone Miner Res · Pubmed #26256109.

ABSTRACT: Protein phosphorylation regulates a wide variety of cellular processes. Thus, we hypothesize that single-nucleotide polymorphisms (SNPs) that may modulate protein phosphorylation could affect osteoporosis risk. Based on a previous conventional genome-wide association (GWA) study, we conducted a three-stage meta-analysis targeting phosphorylation-related SNPs (phosSNPs) for femoral neck (FN)-bone mineral density (BMD), total hip (HIP)-BMD, and lumbar spine (LS)-BMD phenotypes. In stage 1, 9593 phosSNPs were meta-analyzed in 11,140 individuals of various ancestries. Genome-wide significance (GWS) and suggestive significance were defined by α = 5.21 × 10(-6) (0.05/9593) and 1.00 × 10(-4), respectively. In stage 2, nine stage 1-discovered phosSNPs (based on α = 1.00 × 10(-4)) were in silico meta-analyzed in Dutch, Korean, and Australian cohorts. In stage 3, four phosSNPs that replicated in stage 2 (based on α = 5.56 × 10(-3), 0.05/9) were de novo genotyped in two independent cohorts. IDUA rs3755955 and rs6831280, and WNT16 rs2707466 were associated with BMD phenotypes in each respective stage, and in three stages combined, achieving GWS for both FN-BMD (p = 8.36 × 10(-10), p = 5.26 × 10(-10), and p = 3.01 × 10(-10), respectively) and HIP-BMD (p = 3.26 × 10(-6), p = 1.97 × 10(-6), and p = 1.63 × 10(-12), respectively). Although in vitro studies demonstrated no differences in expressions of wild-type and mutant forms of IDUA and WNT16B proteins, in silico analyses predicts that WNT16 rs2707466 directly abolishes a phosphorylation site, which could cause a deleterious effect on WNT16 protein, and that IDUA phosSNPs rs3755955 and rs6831280 could exert indirect effects on nearby phosphorylation sites. Further studies will be required to determine the detailed and specific molecular effects of these BMD-associated non-synonymous variants.

7 Article Osteoporosis medication dispensing for older Australian women from 2002 to 2010: influences of publications, guidelines, marketing activities and policy. 2014

Peeters, Geeske / Tett, Susan E / Duncan, Emma L / Mishra, Gita D / Dobson, Annette J. ·The University of Queensland, School of Population Health, Brisbane, Australia; The University of Queensland, School of Human Movement Studies, Brisbane, Australia. ·Pharmacoepidemiol Drug Saf · Pubmed #25174626.

ABSTRACT: PURPOSE: Developments in anti-osteoporosis medications (AOMs) have led to changes in guidelines and policy, which, along with media and marketing strategies, have had an impact upon the prescribing of AOM. The aim was to examine patterns of AOM dispensing in older women (aged 76-81 years at baseline) from 2002 to 2010. METHODS: Administrative claims data were used to describe AOM dispensing in 4649 participants (born in 1921-1926 and still alive in 2011) in the Australian Longitudinal Study on Women's Health. The patterns were interpreted in the context of changes in guidelines, indications for subsidy, publications (scholarly and general media), and marketing activities. RESULTS: Total use of AOM increased from 134 DDD/1000/day in 2002 to 216 DDD/1000/day in 2007 but then decreased to 184 DDD/1000/day in 2010. Alendronate was the most commonly dispensed AOM but decreased from 2007, while use of risedronate (2002 onward), strontium ranelate (2007 onward) and zoledronic acid (2008 onward) increased. Etidronate and hormone replacement therapy (HRT) prescriptions gradually decreased over time. The decline in alendronate dispensing coincided with increases of other bisphosphonates and publicity about potential adverse effects of bisphosphonates, despite relaxing indications for bone density testing and subsidy for AOM. CONCLUSIONS: Overall dispense of AOM from 2002 reached a peak in 2007 and thereafter declined despite increases in therapeutic options and improved subsidised access. The recent decline in overall AOM dispensing seems to be explained largely by negative publicity rather than specific changes in guidelines and policy.

8 Article Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium. 2014

Moayyeri, Alireza / Hsu, Yi-Hsiang / Karasik, David / Estrada, Karol / Xiao, Su-Mei / Nielson, Carrie / Srikanth, Priya / Giroux, Sylvie / Wilson, Scott G / Zheng, Hou-Feng / Smith, Albert V / Pye, Stephen R / Leo, Paul J / Teumer, Alexander / Hwang, Joo-Yeon / Ohlsson, Claes / McGuigan, Fiona / Minster, Ryan L / Hayward, Caroline / Olmos, José M / Lyytikäinen, Leo-Pekka / Lewis, Joshua R / Swart, Karin M A / Masi, Laura / Oldmeadow, Chris / Holliday, Elizabeth G / Cheng, Sulin / van Schoor, Natasja M / Harvey, Nicholas C / Kruk, Marcin / del Greco M, Fabiola / Igl, Wilmar / Trummer, Olivia / Grigoriou, Efi / Luben, Robert / Liu, Ching-Ti / Zhou, Yanhua / Oei, Ling / Medina-Gomez, Carolina / Zmuda, Joseph / Tranah, Greg / Brown, Suzanne J / Williams, Frances M / Soranzo, Nicole / Jakobsdottir, Johanna / Siggeirsdottir, Kristin / Holliday, Kate L / Hannemann, Anke / Go, Min Jin / Garcia, Melissa / Polasek, Ozren / Laaksonen, Marika / Zhu, Kun / Enneman, Anke W / McEvoy, Mark / Peel, Roseanne / Sham, Pak Chung / Jaworski, Maciej / Johansson, Åsa / Hicks, Andrew A / Pludowski, Pawel / Scott, Rodney / Dhonukshe-Rutten, Rosalie A M / van der Velde, Nathalie / Kähönen, Mika / Viikari, Jorma S / Sievänen, Harri / Raitakari, Olli T / González-Macías, Jesús / Hernández, Jose L / Mellström, Dan / Ljunggren, Osten / Cho, Yoon Shin / Völker, Uwe / Nauck, Matthias / Homuth, Georg / Völzke, Henry / Haring, Robin / Brown, Matthew A / McCloskey, Eugene / Nicholson, Geoffrey C / Eastell, Richard / Eisman, John A / Jones, Graeme / Reid, Ian R / Dennison, Elaine M / Wark, John / Boonen, Steven / Vanderschueren, Dirk / Wu, Frederick C W / Aspelund, Thor / Richards, J Brent / Bauer, Doug / Hofman, Albert / Khaw, Kay-Tee / Dedoussis, George / Obermayer-Pietsch, Barbara / Gyllensten, Ulf / Pramstaller, Peter P / Lorenc, Roman S / Cooper, Cyrus / Kung, Annie Wai Chee / Lips, Paul / Alen, Markku / Attia, John / Brandi, Maria Luisa / de Groot, Lisette C P G M / Lehtimäki, Terho / Riancho, José A / Campbell, Harry / Liu, Yongmei / Harris, Tamara B / Akesson, Kristina / Karlsson, Magnus / Lee, Jong-Young / Wallaschofski, Henri / Duncan, Emma L / O'Neill, Terence W / Gudnason, Vilmundur / Spector, Timothy D / Rousseau, François / Orwoll, Eric / Cummings, Steven R / Wareham, Nick J / Rivadeneira, Fernando / Uitterlinden, Andre G / Prince, Richard L / Kiel, Douglas P / Reeve, Jonathan / Kaptoge, Stephen K. ·Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. ·Hum Mol Genet · Pubmed #24430505.

ABSTRACT: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

9 Article Multistage genome-wide association meta-analyses identified two new loci for bone mineral density. 2014

Zhang, Lei / Choi, Hyung Jin / Estrada, Karol / Leo, Paul J / Li, Jian / Pei, Yu-Fang / Zhang, Yinping / Lin, Yong / Shen, Hui / Liu, Yao-Zhong / Liu, Yongjun / Zhao, Yingchun / Zhang, Ji-Gang / Tian, Qing / Wang, Yu-ping / Han, Yingying / Ran, Shu / Hai, Rong / Zhu, Xue-Zhen / Wu, Shuyan / Yan, Han / Liu, Xiaogang / Yang, Tie-Lin / Guo, Yan / Zhang, Feng / Guo, Yan-fang / Chen, Yuan / Chen, Xiangding / Tan, Lijun / Zhang, Lishu / Deng, Fei-Yan / Deng, Hongyi / Rivadeneira, Fernando / Duncan, Emma L / Lee, Jong Young / Han, Bok Ghee / Cho, Nam H / Nicholson, Geoffrey C / McCloskey, Eugene / Eastell, Richard / Prince, Richard L / Eisman, John A / Jones, Graeme / Reid, Ian R / Sambrook, Philip N / Dennison, Elaine M / Danoy, Patrick / Yerges-Armstrong, Laura M / Streeten, Elizabeth A / Hu, Tian / Xiang, Shuanglin / Papasian, Christopher J / Brown, Matthew A / Shin, Chan Soo / Uitterlinden, André G / Deng, Hong-Wen. ·Center of System Biomedical Sciences, University of Shanghai for Science and Technology, Shanghai, China. ·Hum Mol Genet · Pubmed #24249740.

ABSTRACT: Aiming to identify novel genetic variants and to confirm previously identified genetic variants associated with bone mineral density (BMD), we conducted a three-stage genome-wide association (GWA) meta-analysis in 27 061 study subjects. Stage 1 meta-analyzed seven GWA samples and 11 140 subjects for BMDs at the lumbar spine, hip and femoral neck, followed by a Stage 2 in silico replication of 33 SNPs in 9258 subjects, and by a Stage 3 de novo validation of three SNPs in 6663 subjects. Combining evidence from all the stages, we have identified two novel loci that have not been reported previously at the genome-wide significance (GWS; 5.0 × 10(-8)) level: 14q24.2 (rs227425, P-value 3.98 × 10(-13), SMOC1) in the combined sample of males and females and 21q22.13 (rs170183, P-value 4.15 × 10(-9), CLDN14) in the female-specific sample. The two newly identified SNPs were also significant in the GEnetic Factors for OSteoporosis consortium (GEFOS, n = 32 960) summary results. We have also independently confirmed 13 previously reported loci at the GWS level: 1p36.12 (ZBTB40), 1p31.3 (GPR177), 4p16.3 (FGFRL1), 4q22.1 (MEPE), 5q14.3 (MEF2C), 6q25.1 (C6orf97, ESR1), 7q21.3 (FLJ42280, SHFM1), 7q31.31 (FAM3C, WNT16), 8q24.12 (TNFRSF11B), 11p15.3 (SOX6), 11q13.4 (LRP5), 13q14.11 (AKAP11) and 16q24 (FOXL1). Gene expression analysis in osteogenic cells implied potential functional association of the two candidate genes (SMOC1 and CLDN14) in bone metabolism. Our findings independently confirm previously identified biological pathways underlying bone metabolism and contribute to the discovery of novel pathways, thus providing valuable insights into the intervention and treatment of osteoporosis.

10 Article WNT16 influences bone mineral density, cortical bone thickness, bone strength, and osteoporotic fracture risk. 2012

Zheng, Hou-Feng / Tobias, Jon H / Duncan, Emma / Evans, David M / Eriksson, Joel / Paternoster, Lavinia / Yerges-Armstrong, Laura M / Lehtimäki, Terho / Bergström, Ulrica / Kähönen, Mika / Leo, Paul J / Raitakari, Olli / Laaksonen, Marika / Nicholson, Geoffrey C / Viikari, Jorma / Ladouceur, Martin / Lyytikäinen, Leo-Pekka / Medina-Gomez, Carolina / Rivadeneira, Fernando / Prince, Richard L / Sievanen, Harri / Leslie, William D / Mellström, Dan / Eisman, John A / Movérare-Skrtic, Sofia / Goltzman, David / Hanley, David A / Jones, Graeme / St Pourcain, Beate / Xiao, Yongjun / Timpson, Nicholas J / Smith, George Davey / Reid, Ian R / Ring, Susan M / Sambrook, Philip N / Karlsson, Magnus / Dennison, Elaine M / Kemp, John P / Danoy, Patrick / Sayers, Adrian / Wilson, Scott G / Nethander, Maria / McCloskey, Eugene / Vandenput, Liesbeth / Eastell, Richard / Liu, Jeff / Spector, Tim / Mitchell, Braxton D / Streeten, Elizabeth A / Brommage, Robert / Pettersson-Kymmer, Ulrika / Brown, Matthew A / Ohlsson, Claes / Richards, J Brent / Lorentzon, Mattias. ·Department of Medicine, Human Genetics, McGill University, Montreal, Canada. ·PLoS Genet · Pubmed #22792071.

ABSTRACT: We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of -0.11 standard deviations [SD] per C allele, P = 6.2 × 10(-9)). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (-0.14 SD per C allele, P = 2.3 × 10(-12), and -0.16 SD per G allele, P = 1.2 × 10(-15), respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3 × 10(-9)), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9 × 10(-6) and rs2707466: OR = 1.22, P = 7.2 × 10(-6)). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16(-/-) mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%-61% (6.5 × 10(-13)Natural variation in humans and targeted disruption in mice demonstrate that WNT16 is an important determinant of CBT, BMD, bone strength, and risk of fracture.

11 Article Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. 2012

Estrada, Karol / Styrkarsdottir, Unnur / Evangelou, Evangelos / Hsu, Yi-Hsiang / Duncan, Emma L / Ntzani, Evangelia E / Oei, Ling / Albagha, Omar M E / Amin, Najaf / Kemp, John P / Koller, Daniel L / Li, Guo / Liu, Ching-Ti / Minster, Ryan L / Moayyeri, Alireza / Vandenput, Liesbeth / Willner, Dana / Xiao, Su-Mei / Yerges-Armstrong, Laura M / Zheng, Hou-Feng / Alonso, Nerea / Eriksson, Joel / Kammerer, Candace M / Kaptoge, Stephen K / Leo, Paul J / Thorleifsson, Gudmar / Wilson, Scott G / Wilson, James F / Aalto, Ville / Alen, Markku / Aragaki, Aaron K / Aspelund, Thor / Center, Jacqueline R / Dailiana, Zoe / Duggan, David J / Garcia, Melissa / Garcia-Giralt, Natàlia / Giroux, Sylvie / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Khusainova, Rita / Kim, Ghi Su / Kooperberg, Charles / Koromila, Theodora / Kruk, Marcin / Laaksonen, Marika / Lacroix, Andrea Z / Lee, Seung Hun / Leung, Ping C / Lewis, Joshua R / Masi, Laura / Mencej-Bedrac, Simona / Nguyen, Tuan V / Nogues, Xavier / Patel, Millan S / Prezelj, Janez / Rose, Lynda M / Scollen, Serena / Siggeirsdottir, Kristin / Smith, Albert V / Svensson, Olle / Trompet, Stella / Trummer, Olivia / van Schoor, Natasja M / Woo, Jean / Zhu, Kun / Balcells, Susana / Brandi, Maria Luisa / Buckley, Brendan M / Cheng, Sulin / Christiansen, Claus / Cooper, Cyrus / Dedoussis, George / Ford, Ian / Frost, Morten / Goltzman, David / González-Macías, Jesús / Kähönen, Mika / Karlsson, Magnus / Khusnutdinova, Elza / Koh, Jung-Min / Kollia, Panagoula / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Ljunggren, Östen / Lorenc, Roman S / Marc, Janja / Mellström, Dan / Obermayer-Pietsch, Barbara / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Ridker, Paul M / Rousseau, François / Slagboom, P Eline / Tang, Nelson L S / Urreizti, Roser / Van Hul, Wim / Viikari, Jorma / Zarrabeitia, María T / Aulchenko, Yurii S / Castano-Betancourt, Martha / Grundberg, Elin / Herrera, Lizbeth / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Kwan, Tony / Li, Rui / Luben, Robert / Medina-Gómez, Carolina / Palsson, Stefan Th / Reppe, Sjur / Rotter, Jerome I / Sigurdsson, Gunnar / van Meurs, Joyce B J / Verlaan, Dominique / Williams, Frances M K / Wood, Andrew R / Zhou, Yanhua / Gautvik, Kaare M / Pastinen, Tomi / Raychaudhuri, Soumya / Cauley, Jane A / Chasman, Daniel I / Clark, Graeme R / Cummings, Steven R / Danoy, Patrick / Dennison, Elaine M / Eastell, Richard / Eisman, John A / Gudnason, Vilmundur / Hofman, Albert / Jackson, Rebecca D / Jones, Graeme / Jukema, J Wouter / Khaw, Kay-Tee / Lehtimäki, Terho / Liu, Yongmei / Lorentzon, Mattias / McCloskey, Eugene / Mitchell, Braxton D / Nandakumar, Kannabiran / Nicholson, Geoffrey C / Oostra, Ben A / Peacock, Munro / Pols, Huibert A P / Prince, Richard L / Raitakari, Olli / Reid, Ian R / Robbins, John / Sambrook, Philip N / Sham, Pak Chung / Shuldiner, Alan R / Tylavsky, Frances A / van Duijn, Cornelia M / Wareham, Nick J / Cupples, L Adrienne / Econs, Michael J / Evans, David M / Harris, Tamara B / Kung, Annie Wai Chee / Psaty, Bruce M / Reeve, Jonathan / Spector, Timothy D / Streeten, Elizabeth A / Zillikens, M Carola / Thorsteinsdottir, Unnur / Ohlsson, Claes / Karasik, David / Richards, J Brent / Brown, Matthew A / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·Nat Genet · Pubmed #22504420.

ABSTRACT: Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

12 Article Genome-wide association study using extreme truncate selection identifies novel genes affecting bone mineral density and fracture risk. 2011

Duncan, Emma L / Danoy, Patrick / Kemp, John P / Leo, Paul J / McCloskey, Eugene / Nicholson, Geoffrey C / Eastell, Richard / Prince, Richard L / Eisman, John A / Jones, Graeme / Sambrook, Philip N / Reid, Ian R / Dennison, Elaine M / Wark, John / Richards, J Brent / Uitterlinden, Andre G / Spector, Tim D / Esapa, Chris / Cox, Roger D / Brown, Steve D M / Thakker, Rajesh V / Addison, Kathryn A / Bradbury, Linda A / Center, Jacqueline R / Cooper, Cyrus / Cremin, Catherine / Estrada, Karol / Felsenberg, Dieter / Glüer, Claus-C / Hadler, Johanna / Henry, Margaret J / Hofman, Albert / Kotowicz, Mark A / Makovey, Joanna / Nguyen, Sing C / Nguyen, Tuan V / Pasco, Julie A / Pryce, Karena / Reid, David M / Rivadeneira, Fernando / Roux, Christian / Stefansson, Kari / Styrkarsdottir, Unnur / Thorleifsson, Gudmar / Tichawangana, Rumbidzai / Evans, David M / Brown, Matthew A. ·University of Queensland Diamantina Institute, University of Queensland, Princess Alexandra Hospital, Brisbane, Australia. ·PLoS Genet · Pubmed #21533022.

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 CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 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.

13 Article Secondary prevention of osteoporosis in Australia: analysis of government-dispensed prescription data. 2010

Hollingworth, Samantha A / Gunanti, Inong / Nissen, Lisa M / Duncan, Emma L. ·School of Population Health, The University of Queensland, Herston, Queensland, Australia. s.hollingworth@uq.edu.au ·Drugs Aging · Pubmed #20210370.

ABSTRACT: BACKGROUND: Osteoporosis is a common cause of disability and death in elderly men and women. Until 2007, Australian Government-subsidized use of oral bisphosphonates, raloxifene and calcitriol (1alpha,25-dihydroxycholecalciferol) was limited to secondary prevention (requiring x-ray evidence of previous low-trauma fracture). The cost to the Pharmaceutical Benefits Scheme was substantial (164 million Australian dollars in 2005/6). OBJECTIVE: To examine the dispensed prescriptions for oral bisphosphonates, raloxifene, calcitriol and two calcium products for the secondary prevention of osteoporosis (after previous low-trauma fracture) in the Australian population. METHODS: We analysed government data on prescriptions for oral bisphosphonates, raloxifene, calcitriol and two calcium products from 1995 to 2006, and by sex and age from 2002 to 2006. Prescription counts were converted to defined daily doses (DDD)/1000 population/day. This standardized drug utilization method used census population data, and adjusts for the effects of aging in the Australian population. RESULTS: Total bisphosphonate use increased 460% from 2.19 to 12.26 DDD/1000 population/day between June 2000 and June 2006. The proportion of total bisphosphonate use in June 2006 was 75.1% alendronate, 24.6% risedronate and 0.3% etidronate. Raloxifene use in June 2006 was 1.32 DDD/1000 population/day. The weekly forms of alendronate and risedronate, introduced in 2001 and 2003, respectively, were quickly adopted. Bisphosphonate use peaked at age 80-89 years in females and 85-94 years in males, with 3-fold higher use in females than in males. CONCLUSIONS: Pharmaceutical intervention for osteoporosis in Australia is increasing with most use in the elderly, the population at greatest risk of fracture. However, fracture prevalence in this population is considerably higher than prescribing of effective anti-osteoporosis medications, representing a missed opportunity for the quality use of medicines.