Journal
PLOS GENETICS
Volume 7, Issue 4, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1001372
Keywords
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Categories
Funding
- National Health and Medical Research Council (Australia) [511132, 569807]
- Australian Cancer Research Foundation
- Rebecca Cooper Foundation (Australia)
- National Health and Medical Research Council (Australia)
- Medical Research Council [MRC G0800582, G0600702]
- Wellcome Trust [WT083431MA]
- Health Research Council of New Zealand
- Sanofi-Aventis
- Eli Lilly
- Novartis
- Pfizer
- Proctor
- Gamble Pharmaceuticals
- Roche
- Medical Research Council (UK) [MRC G0600702]
- Netherlands Organisation of Scientific Research NWO [175.010.2005.011, 911-03-012]
- Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]
- Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) [050-060-810]
- Erasmus Medical Center
- Erasmus University, Rotterdam
- Netherlands Organization for the Health Research and Development (ZonMw)
- Research Institute for Diseases in the Elderly (RIDE)
- Ministry of Education, Culture, and Science
- Ministry for Health, Welfare and Sports
- European Commission
- Municipality of Rotterdam
- German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]
- National Health and Medical Research Council, Australia
- Australian National Health and Medical Research Council
- MBF Living Well foundation
- Ernst Heine Family Foundation
- Amgen
- Eli Lilly International
- GE-Lunar
- Merck Australia
- Sanofi-Aventis Australia
- Servier
- Healthway Health Promotion Foundation of Western Australia
- Australasian Menopause Society
- National Health and Medical Research Council
- Medical research Council UK
- Arthritis Research UK
- Canadian Institutes of Health Research
- Canadian Foundation for Innovation
- Fonds de la Recherche en Sante Quebec
- Lady Davis Institute
- Ministere du Developpemente conomique
- innovation et exportation du Quebec
- Chronic Disease Research Foundation
- European Society for Clinical and Economic aspects of Osteoporosis
- European Union
- National Institute for Health Research
- Victorian Health Promotion Foundation
- Geelong Region Medical Research Foundation
- National Health and Medical Research Council, Australia [628582]
- Action Research UK
- MRC [G0600702, G1000467, MC_U142684172, MC_U142684175, G0600705, G9825289, MC_U142661184, G0800582] Funding Source: UKRI
- Medical Research Council [G1000467, U1475000001, MC_U142684175, MC_U142684172, G0800582, G0600705, G9825289, G0600702, MC_UP_A620_1014, MC_U142661184] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0508-10082] Funding Source: researchfish
- Versus Arthritis [17489] Funding Source: researchfish
Ask authors/readers for more resources
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 zscores 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.
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