Abstract
Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P 5 × 10 8), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.
| Original language | English |
|---|---|
| Pages (from-to) | 1199-1206 |
| Number of pages | 8 |
| Journal | Nature Genetics |
| Volume | 41 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2009 |
| Externally published | Yes |
Bibliographical note
Funding Information:We thank all study participants for making this work possible. This research and the Genetic Factors for Osteoporosis (GEFOS) consortium (http://www.gefos. org) have been funded by the European Commission (HEALTH-F2-2008-201865-GEFOS). Rotterdam Study (RS): This study was funded by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2) and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project 050-060-810. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the GWAS database. 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 thank the staff from the Rotterdam Study, particularly L. Buist and J.H. van den Boogert and also the participating general practitioners and pharmacists. Erasmus Rucphen Family (ERF): The study was supported by grants from the Netherlands Organization for Scientific Research (NWO), Erasmus MC and the Centre for Medical Systems Biology (CMSB). We thank all general practitioners for their contributions, P. Veraart for help in genealogy, J. Vergeer for supervision of the laboratory work and P. Snijders for help in data collection. Twins UK (TUK): The study was funded by the Wellcome Trust, the Arthritis Research Campaign, the Chronic Disease Research Foundation, the Canadian Institutes of Health Research (J.B.R.), the European Society for Clinical and Economic Aspects of Osteoporosis (J.B.R.) and the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff of the Twins UK study; the DNA Collections and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation; Quality Control of the Twins UK cohort for genotyping (in particular A. Chaney, R. Ravindrarajah, D. Simpkin, C. Hinds and T. Dibling); P. Martin and S. Potter of the DNA and Genotyping Informatics teams for data handling; Le Centre National de Génotypage, France, led by M. Lathrop, for genotyping; Duke University, North Carolina, USA, led by D. Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by A. Palotie. Icelandic deCODE Study (dCG): We thank the staff of the deCODE core facilities and recruitment centre for their important contributions to this work. Framingham Osteoporosis Study (FOS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR/AG 41398; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR).
Funding
We thank all study participants for making this work possible. This research and the Genetic Factors for Osteoporosis (GEFOS) consortium (http://www.gefos. org) have been funded by the European Commission (HEALTH-F2-2008-201865-GEFOS). Rotterdam Study (RS): This study was funded by the Netherlands Organization of Scientific Research NWO Investments (175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2) and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) project 050-060-810. We thank P. Arp, M. Jhamai, M. Moorhouse, M. Verkerk and S. Bervoets for their help in creating the GWAS database. 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 thank the staff from the Rotterdam Study, particularly L. Buist and J.H. van den Boogert and also the participating general practitioners and pharmacists. Erasmus Rucphen Family (ERF): The study was supported by grants from the Netherlands Organization for Scientific Research (NWO), Erasmus MC and the Centre for Medical Systems Biology (CMSB). We thank all general practitioners for their contributions, P. Veraart for help in genealogy, J. Vergeer for supervision of the laboratory work and P. Snijders for help in data collection. Twins UK (TUK): The study was funded by the Wellcome Trust, the Arthritis Research Campaign, the Chronic Disease Research Foundation, the Canadian Institutes of Health Research (J.B.R.), the European Society for Clinical and Economic Aspects of Osteoporosis (J.B.R.) and the European Union FP-5 GenomEUtwin Project (QLG2-CT-2002-01254). The study also receives support from a National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London. We thank the staff of the Twins UK study; the DNA Collections and Genotyping Facilities at the Wellcome Trust Sanger Institute for sample preparation; Quality Control of the Twins UK cohort for genotyping (in particular A. Chaney, R. Ravindrarajah, D. Simpkin, C. Hinds and T. Dibling); P. Martin and S. Potter of the DNA and Genotyping Informatics teams for data handling; Le Centre National de Génotypage, France, led by M. Lathrop, for genotyping; Duke University, North Carolina, USA, led by D. Goldstein, for genotyping; and the Finnish Institute of Molecular Medicine, Finnish Genome Center, University of Helsinki, led by A. Palotie. Icelandic deCODE Study (dCG): We thank the staff of the deCODE core facilities and recruitment centre for their important contributions to this work. Framingham Osteoporosis Study (FOS): The study was funded by grants from the US National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Aging (R01 AR/AG 41398; DPK and R01 AR 050066; DK). The Framingham Heart Study of the National Heart, Lung, and Blood Institute of the National Institutes of Health and Boston University School of Medicine were supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix, Inc. for genotyping services (N02-HL-6-4278). Analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. eQTL HOb Study: The study was supported by Genome Quebec, Genome Canada and the Canadian Institutes of Health Research (CIHR).
| Funders | Funder number |
|---|---|
| Arthritis Research Campaign | |
| European Society for Clinical and Economic Aspects of Osteoporosis | |
| European Union FP-5 GenomEUtwin Project | QLG2-CT-2002-01254 |
| Genome Quebec | |
| Netherlands Genomics Initiative | |
| Netherlands Organization of Scientific Research NWO | 175.010.2005.011, 911-03-012 |
| RIDE2 | |
| Research Institute for Diseases in the Elderly | 014-93-015 |
| Robert Dawson Evans Endowment | |
| National Institute on Aging | R01 AR/AG 41398, R01 AR 050066 |
| National Heart, Lung, and Blood Institute | N01-HC-25195, R01HL064278 |
| National Institute of Arthritis and Musculoskeletal and Skin Diseases | |
| Genome Canada | |
| Wellcome Trust | |
| NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research | |
| Canadian Institutes of Health Research | |
| National Institute for Health and Care Research | |
| European Commission | HEALTH-F2-2008-201865-GEFOS |
| ZonMw | |
| Erasmus Universiteit Rotterdam | |
| Ministerie van Volksgezondheid, Welzijn en Sport | |
| Erasmus Medisch Centrum | |
| Ministerie van Onderwijs, Cultuur en Wetenschap | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | 050-060-810 |
| Centre for Medical Systems Biology |