Pick Topic
Review Topic
List Experts
Examine Expert
Save Expert
  Site Guide ··   
Osteoporosis: HELP
Articles by Stephen K. Kaptoge
Based on 11 articles published since 2008
||||

Between 2008 and 2019, S. Kaptoge wrote the following 11 articles about Osteoporosis.
 
+ Citations + Abstracts
1 Article An atlas of genetic influences on osteoporosis in humans and mice. 2019

Morris, John A / Kemp, John P / Youlten, Scott E / Laurent, Laetitia / Logan, John G / Chai, Ryan C / Vulpescu, Nicholas A / Forgetta, Vincenzo / Kleinman, Aaron / Mohanty, Sindhu T / Sergio, C Marcelo / Quinn, Julian / Nguyen-Yamamoto, Loan / Luco, Aimee-Lee / Vijay, Jinchu / Simon, Marie-Michelle / Pramatarova, Albena / Medina-Gomez, Carolina / Trajanoska, Katerina / Ghirardello, Elena J / Butterfield, Natalie C / Curry, Katharine F / Leitch, Victoria D / Sparkes, Penny C / Adoum, Anne-Tounsia / Mannan, Naila S / Komla-Ebri, Davide S K / Pollard, Andrea S / Dewhurst, Hannah F / Hassall, Thomas A D / Beltejar, Michael-John G / Anonymous11331162 / Adams, Douglas J / Vaillancourt, Suzanne M / Kaptoge, Stephen / Baldock, Paul / Cooper, Cyrus / Reeve, Jonathan / Ntzani, Evangelia E / Evangelou, Evangelos / Ohlsson, Claes / Karasik, David / Rivadeneira, Fernando / Kiel, Douglas P / Tobias, Jonathan H / Gregson, Celia L / Harvey, Nicholas C / Grundberg, Elin / Goltzman, David / Adams, David J / Lelliott, Christopher J / Hinds, David A / Ackert-Bicknell, Cheryl L / Hsu, Yi-Hsiang / Maurano, Matthew T / Croucher, Peter I / Williams, Graham R / Bassett, J H Duncan / Evans, David M / Richards, J Brent. ·Department of Human Genetics, McGill University, Montréal, Québec, Canada. · Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. · Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK. · Institute for Systems Genetics, New York University Langone Medical Center, New York, NY, USA. · Department of Research, 23andMe, Inc., Mountain View, CA, USA. · Research Institute of the McGill University Health Centre, Montréal, Québec, Canada. · McGill University and Genome Quebec Innovation Centre, Montréal, Québec, Canada. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. · Department of Biomedical Genetics, University of Rochester, Rochester, NY, USA. · Department of Orthopedics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. · Department of Medicine, McGill University, Montréal, Québec, Canada. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. · NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. · NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. · Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece. · Center for Evidence Synthesis in Health, Department of Health Services, Policy and Practice, School of Public Health, Brown University, Providence, RI, USA. · Department of Epidemiology and Biostatistics, Imperial College London, London, UK. · Department of Internal Medicine and Clinical Nutrition, University of Gothenburg, Gothenburg, Sweden. · Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA. · Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA. · Department of Medicine, Harvard Medical School, Boston, MA, USA. · Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, USA. · Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK. · Children's Mercy Hospitals and Clinics, Kansas City, MO, USA. · Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK. · Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, NY, USA. · University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. d.evans1@uq.edu.au. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. d.evans1@uq.edu.au. · Department of Human Genetics, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Medicine, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montréal, Québec, Canada. brent.richards@mcgill.ca. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. brent.richards@mcgill.ca. ·Nat Genet · Pubmed #30598549.

ABSTRACT: Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10

2 Article Identification of 153 new loci associated with heel bone mineral density and functional involvement of GPC6 in osteoporosis. 2017

Kemp, John P / Morris, John A / Medina-Gomez, Carolina / Forgetta, Vincenzo / Warrington, Nicole M / Youlten, Scott E / Zheng, Jie / Gregson, Celia L / Grundberg, Elin / Trajanoska, Katerina / Logan, John G / Pollard, Andrea S / Sparkes, Penny C / Ghirardello, Elena J / Allen, Rebecca / Leitch, Victoria D / Butterfield, Natalie C / Komla-Ebri, Davide / Adoum, Anne-Tounsia / Curry, Katharine F / White, Jacqueline K / Kussy, Fiona / Greenlaw, Keelin M / Xu, Changjiang / Harvey, Nicholas C / Cooper, Cyrus / Adams, David J / Greenwood, Celia M T / Maurano, Matthew T / Kaptoge, Stephen / Rivadeneira, Fernando / Tobias, Jonathan H / Croucher, Peter I / Ackert-Bicknell, Cheryl L / Bassett, J H Duncan / Williams, Graham R / Richards, J Brent / Evans, David M. ·University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia. · MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK. · Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, Québec, Canada. · Department of Human Genetics, McGill University, Montréal, Québec, Canada. · Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands. · Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands. · Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, Western Australia, Australia. · Garvan Institute of Medical Research, Sydney, New South Wales, Australia. · St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia. · Musculoskeletal Research Unit, Department of Translational Health Sciences, University of Bristol, Bristol, UK. · Molecular Endocrinology Laboratory, Department of Medicine, Imperial College London, London, UK. · Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK. · Donnelly Center for Cellular and Biomedical Research, University of Toronto, Toronto, Ontario, Canada. · MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK. · NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK. · NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. · Gerald Bronfman Department of Oncology, McGill University, Montréal, Québec, Canada. · Department of Epidemiology, Biostatistics &Occupational Health, McGill University, Montréal, Québec, Canada. · Department of Pathology and Institute for Systems Genetics, New York University Langone Medical Center, New York, New York, USA. · Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. · Strangeways Research Laboratory, Cambridge, UK. · School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales, Australia. · Center for Musculoskeletal Research, Department of Orthopaedics, University of Rochester, Rochester, New York, USA. · Department of Twin Research and Genetic Epidemiology, King's College London, London, UK. ·Nat Genet · Pubmed #28869591.

ABSTRACT: Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.

3 Article Degenerative inter-vertebral disc disease osteochondrosis intervertebralis in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over. 2017

Armbrecht, Gabriele / Felsenberg, Dieter / Ganswindt, Melanie / Lunt, Mark / Kaptoge, Stephen K / Abendroth, Klaus / Aroso Dias, Antonio / Bhalla, Ashok K / Cannata Andia, Jorge / Dequeker, Jan / Eastell, Richard / Hoszowski, Krzysztof / Lyritis, George / Masaryk, Pavol / van Meurs, Joyce / Miazgowski, Tomasz / Nuti, Ranuccio / Poór, Gyula / Redlund-Johnell, Inga / Reid, David M / Schatz, Helmut / Todd, Christopher J / Woolf, Anthony D / Rivadeneira, Fernando / Javaid, Muhammad K / Cooper, Cyrus / Silman, Alan J / O'Neill, Terence W / Reeve, Jonathan / Anonymous480903. ·Department of Radiology and Nuclear Medicine, Free University, Berlin, Germany. · NIHR Musculoskeletal Biomedical Research Unit, Central Manchester University Hospitals NHS Foundation Trust, & Arthritis Research UK Centre for Epidemiology, Manchester, University of Manchester. · Department of Public Health and Primary Care, Strangeways Research Laboratory, Cambridge, UK. · Klinik fur Innere Medezin IV, Jena, Germany. · Rheumatology, Hospital de San Joao, Oporto, Portugal. · Rheumatology, Royal National Hospital for Rheumatic Diseases, Bath, UK. · Nephrology, Asturias General Hospital, Oviedo, Spain. · Rheumatology, University Hospital, Leuven, Belgium. · Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK. · Medicine, PKP Hospital, Warsaw, Poland. · Laboratory for the Research of Musculoskeletal System, University of Athens, Athens, Greece. · Rheumatology, Institute of Rheumatic Diseases, Piestany, Slovakia. · Department of Epidemiology and Department of Internal Medicine, Erasmus University, Rotterdam, Netherlands. · Department of Hypertension and Internal Medicine, Pomeranian Medical University, Szczecin, Poland. · Institute of Clinical Medicine, University of Siena, Siena, Italy. · 1st Department of Rheumatology and Metabolic Osteology, National Institute of Rheumatology and Physiotherapy, Budapest, Hungary. · Orthopaedics and Radiology, Malmö General Hospital, Malmö, Sweden. · School of Medicine, Medical Science and Nutrition, University of Aberdeen, Aberdeen, UK. · Rheumatology, Med Klinik & Polyklinik, Bochum, Germany. · School of Health Sciences, The University of Manchester, Oxford Road, Manchester. · Institute of Health Care Research, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth, Royal Cornwall Hospital, Truro. · Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, NIHR Musculo-skeletal Biomedical Research Unit, Botnar Research Centre, Oxford, UK. ·Rheumatology (Oxford) · Pubmed #28398504.

ABSTRACT: Objectives: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time. Methods: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature. Results: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD. Conclusion: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes.

4 Article Predictive ability of heel quantitative ultrasound for incident fractures: an individual-level meta-analysis. 2015

McCloskey, E V / Kanis, J A / Odén, A / Harvey, N C / Bauer, D / González-Macias, J / Hans, D / Kaptoge, S / Krieg, M A / Kwok, T / Marin, F / Moayyeri, A / Orwoll, E / Gluёr, C / Johansson, H. ·Academic Unit of Bone Metabolism and Mellanby Centre for Bone Research, University of Sheffield, Metabolic Bone Centre, Northern General Hospital, Herries Road, Sheffield, S5 7AU, UK, e.v.mccloskey@sheffield.ac.uk. ·Osteoporos Int · Pubmed #25690339.

ABSTRACT: INTRODUCTION: The aim of this meta-analysis was to investigate the association between parameters of QUS and risk of fracture. METHODS: In an individual-level analysis, we studied participants in nine prospective cohorts from Asia, Europe and North America. Heel broadband ultrasonic attenuation (BUA dB/MHz) and speed of sound (SOS m/s) were measured at baseline. Fractures during follow-up were collected by self-report and in some cohorts confirmed by radiography. An extension of Poisson regression was used to examine the gradient of risk (GR, hazard ratio per 1 SD decrease) between QUS and fracture risk adjusted for age and time since baseline in each cohort. Interactions between QUS and age and time since baseline were explored. RESULTS: Baseline measurements were available in 46,124 men and women, mean age 70 years (range 20-100). Three thousand and eighteen osteoporotic fractures (787 hip fractures) occurred during follow-up of 214,000 person-years. The summary GR for osteoporotic fracture was similar for both BUA (1.45, 95 % confidence intervals (CI) 1.40-1.51) and SOS (1.42, 95 % CI 1.36-1.47). For hip fracture, the respective GRs were 1.69 (95 % CI, 1.56-1.82) and 1.60 (95 % CI, 1.48-1.72). However, the GR was significantly higher for both fracture outcomes at lower baseline BUA and SOS (p < 0.001). The predictive value of QUS was the same for men and women and for all ages (p > 0.20), but the predictive value of both BUA and SOS for osteoporotic fracture decreased with time (p = 0.018 and p = 0.010, respectively). For example, the GR of BUA for osteoporotic fracture, adjusted for age, was 1.51 (95 % CI 1.42-1.61) at 1 year after baseline, but at 5 years, it was 1.36 (95 % CI 1.27-1.46). CONCLUSIONS: Our results confirm that quantitative ultrasound is an independent predictor of fracture for men and women particularly at low QUS values.

5 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.

6 Article A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus. 2014

Oei, Ling / Hsu, Yi-Hsiang / Styrkarsdottir, Unnur / Eussen, Bert H / de Klein, Annelies / Peters, Marjolein J / Halldorsson, Bjarni / Liu, Ching-Ti / Alonso, Nerea / Kaptoge, Stephen K / Thorleifsson, Gudmar / Hallmans, Göran / Hocking, Lynne J / Husted, Lise Bjerre / Jameson, Karen A / Kruk, Marcin / Lewis, Joshua R / Patel, Millan S / Scollen, Serena / Svensson, Olle / Trompet, Stella / van Schoor, Natasja M / Zhu, Kun / Buckley, Brendan M / Cooper, Cyrus / Ford, Ian / Goltzman, David / González-Macías, Jesús / Langdahl, Bente Lomholt / Leslie, William D / Lips, Paul / Lorenc, Roman S / Olmos, José M / Pettersson-Kymmer, Ulrika / Reid, David M / Riancho, José A / Slagboom, P Eline / Garcia-Ibarbia, Carmen / Ingvarsson, Thorvaldur / Johannsdottir, Hrefna / Luben, Robert / Medina-Gómez, Carolina / Arp, Pascal / Nandakumar, Kannabiran / Palsson, Stefan Th / Sigurdsson, Gunnar / van Meurs, Joyce B J / Zhou, Yanhua / Hofman, Albert / Jukema, J Wouter / Pols, Huibert A P / Prince, Richard L / Cupples, L Adrienne / Marshall, Christian R / Pinto, Dalila / Sato, Daisuke / Scherer, Stephen W / Reeve, Jonathan / Thorsteinsdottir, Unnur / Karasik, David / Richards, J Brent / Stefansson, Kari / Uitterlinden, André G / Ralston, Stuart H / Ioannidis, John P A / Kiel, Douglas P / Rivadeneira, Fernando / Estrada, Karol. ·Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. ·J Med Genet · Pubmed #24343915.

ABSTRACT: BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

7 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.

8 Article Estimation of absolute fracture risk among middle-aged and older men and women: the EPIC-Norfolk population cohort study. 2009

Moayyeri, Alireza / Kaptoge, Stephen / Luben, Robert N / Wareham, Nicholas J / Bingham, Sheila / Reeve, Jonathan / Khaw, Kay Tee. ·Department of Public Health and Primary Care, Institute of Public Health, Strangeways Research Laboratory, University of Cambridge, Worts Causeway, Cambridge, UK. am700@cam.ac.uk ·Eur J Epidemiol · Pubmed #19350399.

ABSTRACT: While estimates of relative risks associated with risk factors such as age and bone mineral density (BMD) may be of interest for etiologic and comparative purposes, clinical questions such as who might benefit most from preventive interventions or BMD monitoring depend on estimates of absolute fracture risk. The European prospective investigation into cancer (EPIC)-Norfolk study included 25,311 participants (11,476 men) aged 4,079 years in 1993-1997. All participants were followed for osteoporotic fractures to March 2007. Ten-year absolute risk of fracture in men and women were calculated using the baseline survivor function in multivariable Cox proportional-hazards models adjusting for age, sex, history of fractures, body mass index, smoking, and alcohol intake. In comparison of those without history of fracture versus those with history of fracture, the 10-year absolute risk of any fracture in men ranged from 1.0 vs. 1.2% at age 40 years to 3.0 vs. 4.4% at age 75 years. The respective estimates in women ranged from 0.7 vs. 1.0% at age 40 years to 9.3 vs. 17.2% at age 75 years. Statistically significant interaction between age and sex was found (P < 0.001), which contributed to the differences in predicted absolute fracture risks for men and women at different ages. Our study shows the need for population-specific data to develop efficient well calibrated algorithms for assessment of fracture risk. The interaction observed between sex and age points to the need for further prospective studies among men.

9 Article Prediction of incident hip fracture risk by femur geometry variables measured by hip structural analysis in the study of osteoporotic fractures. 2008

Kaptoge, Stephen / Beck, Thomas J / Reeve, Jonathan / Stone, Katie L / Hillier, Teresa A / Cauley, Jane A / Cummings, Steven R. ·Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom. stephen@srl.cam.ac.uk ·J Bone Miner Res · Pubmed #18684092.

ABSTRACT: The role of bone tissue's geometric distribution in hip fracture risk requires full evaluation in large population-based datasets. We tested whether section modulus, a geometric index of bending strength, predicted hip fracture better than BMD. Among 7474 women from the Study of Osteoporotic Fractures (SOF) with hip DXA scans at baseline, there were 635 incident hip fractures recorded over 13 yr. Hip structural analysis software was used to derive variables from the DXA scans at the narrow neck (NN), intertrochanter (IT), and shaft (S) regions. Associations of derived structural variables with hip fracture were assessed using Cox proportional hazard modeling. Hip fracture prediction was assessed using the C-index concordance statistic. Incident hip fracture cases had larger neck-shaft angles, larger subperiosteal and estimated endosteal diameters, greater distances from lateral cortical margin to center of mass (lateral distance), and higher estimated buckling ratios (p < 0.0001 for each). Areal BMD, cross-sectional area, cross-sectional moment of inertia, section modulus, estimated cortical thickness, and centroid position were all lower in hip fracture cases (p < 0.044). In hip fracture prediction using NN region parameters, estimated cortical thickness, areal BMD, and estimated buckling ratio were equivalent (C-index = 0.72; 95% CI, 0.70, 0.74), but section modulus performed less well (C-index = 0.61; 95% CI, 0.58, 0.63; p < 0.0001 for difference). In multivariable models combining hip structural analysis variables and age, effects of bone dimensions (i.e., lateral distance, subperiosteal diameter, and estimated endosteal width) were interchangeable, whereas age and neck-shaft angle were independent predictors. Several parsimonious multivariable models that were prognostically equivalent for the NN region were obtained combining a measure of width, a measure of mass, age, and neck-shaft angle (BMD is a ratio of mass to width in the NN region; C-index = 0.77; 95% CI, 0.75, 0.79). Trochanteric fractures were best predicted by analysis of the IT region. Because section modulus failed to predict hip fracture risk as well as areal BMD, the thinner cortices and wider bones among those who fractured may imply that simple failure in bending is not the usual event in fracture. Fracture might require initiation (e.g., by localized crushing or buckling of the lateral cortex).

10 Article Geographical variation in DXA bone mineral density in young European men and women. Results from the Network in Europe on Male Osteoporosis (NEMO) study. 2008

Kaptoge, Stephen / da Silva, Jose A / Brixen, Kim / Reid, David M / Kröger, Heikki / Nielsen, Torben L / Andersen, Marianne / Hagen, Claus / Lorenc, Roman / Boonen, Steven / de Vernejoul, Marie-Christine / Stepan, Jan J / Adams, Judith / Kaufman, Jean-Marc / Reeve, Jonathan. ·Department of Medicine and Strangeways Research Laboratory, University of Cambridge, Wort's Causeway, Cambridge CB1 8RN, UK. stephen@srl.cam.ac.uk ·Bone · Pubmed #18519175.

ABSTRACT: INTRODUCTION: It remains unclear whether young normal BMD reference values specific to an American population can be validly used for T-score calculation in Europeans. METHODS: We collected population based BMD data from 1163 men and 329 women aged 19-29 years from 17 centres across Europe to compare mean and SD values with the NHANES-III study USA results. BMD(g/cm2) was measured at the hip and spine using DXA densitometers cross-calibrated with the European Spine Phantom (ESP). The only exclusions were for technically inadequate scans. A linear regression model was used to derive reference values. To allow for direct comparison with published NHANES III study data, the cross-calibrated BMD values were converted using the ESP equations to Hologic QDR 1000 units. RESULTS: In men, the overall mean(SD) BMD values expressed in Hologic-QDR1000 units of measurement, were: femoral neck 0.912(0.132); trochanter 0.793(0.124); and L2-L4 spine 1.027(0.123). The respective estimates in women were: 0.826(0.115); 0.670(0.093); and 0.983(0.107). However the I2 statistic for heterogeneity indicated moderate to strong evidence of between-centre heterogeneity. There was, however, no significant heterogeneity observed between centres within countries, suggesting that this variation arose from national differences. Compared to the NHANES III population-based US data, the mean values in women were significantly lower at both sites due to some lower national European means. However, at all sites and in both sexes the SD's were very similar between the US and Europe. There was some evidence that recruiting volunteers resulted in biased values in women. CONCLUSION: Our T-score normal values for the lumbar spine (L2-L4) should be more reliable for spine-specific risk assessment than some non-representative normal ranges, and should be evaluated for that purpose in Europe. If T-scores are to be used to compare individual data with ranges seen in normal young subjects of the same nationality, it may be necessary to adjust femoral NHANES III-based T-scores by adding (or subtracting) a country-specific adjustment factor. In risk assessment it is probably sufficient to use NHANES III-based hip T-scores, as supplied for the hip by densitometer manufacturers, interpreting them in light of recent international meta-analysis data on the relationship between BMD and fracture risk.

11 Article Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis. 2008

van Meurs, Joyce B J / Trikalinos, Thomas A / Ralston, Stuart H / Balcells, Susana / Brandi, Maria Luisa / Brixen, Kim / Kiel, Douglas P / Langdahl, Bente L / Lips, Paul / Ljunggren, Osten / Lorenc, Roman / Obermayer-Pietsch, Barbara / Ohlsson, Claes / Pettersson, Ulrika / Reid, David M / Rousseau, Francois / Scollen, Serena / Van Hul, Wim / Agueda, Lidia / Akesson, Kristina / Benevolenskaya, Lidia I / Ferrari, Serge L / Hallmans, Göran / Hofman, Albert / Husted, Lise Bjerre / Kruk, Marcin / Kaptoge, Stephen / Karasik, David / Karlsson, Magnus K / Lorentzon, Mattias / Masi, Laura / McGuigan, Fiona E A / Mellström, Dan / Mosekilde, Leif / Nogues, Xavier / Pols, Huibert A P / Reeve, Jonathan / Renner, Wilfried / Rivadeneira, Fernando / van Schoor, Natasja M / Weber, Kurt / Ioannidis, John P A / Uitterlinden, André G / Anonymous140595. ·Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. ·JAMA · Pubmed #18349089.

ABSTRACT: CONTEXT: Mutations in the low-density lipoprotein receptor-related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect osteoporosis risk in the general population. OBJECTIVE: To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING: Prospective, multicenter, collaborative study of individual-level data on 37,534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES: Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS: The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25,052 [number of participants with available data]; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 10(-6)) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.08-1.47 for Met667 [2001 fractures among 20 488 individuals] and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 [1988 fractures among 20,096 individuals]). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele [7876 fractures among 31,435 individuals)]) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele [7802 fractures among 31 199 individuals]). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS: Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance [herein, unadjusted P < 10(-7)] that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.