Journal article

Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

Emma L Duncan, Patrick Danoy, John P Kemp, Paul J Leo, Eugene McCloskey, Geoffrey C Nicholson, Richard Eastell, Richard L Prince, John A Eisman, Graeme Jones, Philip N Sambrook, Ian R Reid, Elaine M Dennison, John Wark, J Brent Richards, Andre G Uitterlinden, Tim D Spector, Chris Esapa, Roger D Cox, Steve DM Brown Show all

PLoS Genetics | PUBLIC LIBRARY SCIENCE | Published : 2011

Abstract

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55-85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or -4.0 to -1.5, n = 900), with replication in cohorts of women drawn from the gener..

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Grants

Awarded by National Health and Medical Research Council (Australia)


Awarded by Medical Research Council


Awarded by Wellcome Trust


Awarded by Medical Research Council (UK)


Awarded by Netherlands Organisation of Scientific Research NWO


Awarded by Research Institute for Diseases in the Elderly (RIDE2)


Awarded by Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO)


Awarded by German Bundesministerium fuer Forschung und Technology


Awarded by National Health and Medical Research Council, Australia


Awarded by National Institute for Health Research


Awarded by Versus Arthritis


Funding Acknowledgements

This study was funded by the National Health and Medical Research Council (Australia) (grant reference 511132). Funding was also received from the Australian Cancer Research Foundation and Rebecca Cooper Foundation (Australia). MAB is funded by a National Health and Medical Research Council (Australia) Principal Research Fellowship and ELD is funded by a National Health and Medical Research Council (Australia) Career Development Award (569807). DME is supported by a Medical Research Council New Investigator Award (MRC G0800582). JPK is funded by a Wellcome Trust 4-year PhD studentship in molecular, genetic, and life course epidemiology (WT083431MA). IRR is supported by the Health Research Council of New Zealand. The OPUS study was supported by Sanofi-Aventis, Eli Lilly, Novartis, Pfizer, Proctor and Gamble Pharmaceuticals, and Roche. CE, RDC, SDMB, RVT, and MAB are supported by a Medical Research Council (UK) grant (MRC G0600702). The generation and management of GWAS genotype data for the Rotterdam Study were supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012); the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. We would like to thank Dr. Tobias A. Knoch, Luc V. de Zeeuw, Anis Abuseiris, and Rob de Graaf, as well as their institutions the Erasmus Computing Grid, Rotterdam, The Netherlands, and especially the national German MediGRID and Services@MediGRID part of the German D-Grid, both funded by the German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and #01 IG 07015 G for access to their grid resources. The Sydney Twin Study and Tasmanian Older Adult Cohort were supported by the National Health and Medical Research Council, Australia. The Dubbo Osteoporosis Epidemiology Study was supported by the Australian National Health and Medical Research Council, MBF Living Well foundation, the Ernst Heine Family Foundation, and from untied educational grants from Amgen, Eli Lilly International, GE-Lunar, Merck Australia, Novartis, Sanofi-Aventis Australia, and Servier. The Calcium Intake Fracture Outcome Study was supported by Healthway Health Promotion Foundation of Western Australia, the Australasian Menopause Society, and the National Health and Medical Research Council. The Hertfordshire Cohort Study was supported by grants from the Medical research Council UK and Arthritis Research UK. JBR has received support from the Canadian Institutes of Health Research, Canadian Foundation for Innovation, Fonds de la Recherche en Sante Quebec, Lady Davis Institute, and Ministere du Developpemente conomique, innovation et exportation du Quebec. The Twins UK study is supported by The Wellcome Trust, Arthritis Research UK, the Chronic Disease Research Foundation, the Canadian Institutes of Health Research, the European Society for Clinical and Economic aspects of Osteoporosis, the European Union GenomEUtwin Project, and the National Institute for Health Research.The Geelong Osteoporosis Study was funded by grants from the Victorian Health romotion Foundation and the Geelong Region Medical Research Foundation and by the National Health and Medical Research Council, Australia (project grant 628582). The Oxford Osteoporosis Study was funded by Action Research UK. The ENU mutagenesis program is supported by the Medical research council project grant G0600702. The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript.