☆ 4.5 Article

Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study

BMJ-BRITISH MEDICAL JOURNAL (2018)

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Journal

BMJ-BRITISH MEDICAL JOURNAL
Volume 362, Issue -, Pages -

Publisher

BMJ PUBLISHING GROUP
DOI: 10.1136/bmj.k3225

Keywords

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Categories

Medicine, General & Internal

Funding

  1. European Commission [HEALTH-F2-2008-201865-GEFOS]
  2. NIH [N01AG-12100]
  3. NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association)
  4. Althingi (the Icelandic Parliament)
  5. Icelandic Heart Association
  6. Anglo-Australasian Osteoporosis Genetics Consortium (AOGC): National Health and Medical Research Council (Australia) [511132]
  7. Australian Cancer Research Foundation (Australia)
  8. National Health and Medical Research Council (Australia)
  9. National Health and Medical Research Council (Australia) Career Development Award [569807]
  10. Medical Research Council New Investigator Award [MRC G0800582]
  11. Health Research Council of New Zealand.
  12. Sanofi-Aventis
  13. Eli Lilly
  14. Novartis
  15. Pfizer
  16. Proctor & Gamble Pharmaceutical
  17. Roche
  18. National Health and Medical Research Council, Australia
  19. Rebecca Cooper Foundation (Australia)
  20. Australian National Health and Medical Research Council
  21. MBF Living Well foundation
  22. Ernst Heine Family Foundation
  23. Amgen
  24. Eli Lilly International
  25. GE-Lunar
  26. Merck Australia
  27. Sanofi-Aventis Australia
  28. Servier
  29. Medical Research Council UK
  30. Arthritis Research UK
  31. The Victorian Health Promotion Foundation
  32. Geelong Region Medical Research Foundation
  33. National Health and Medical Research Council, Australia [628582]
  34. Action Research UK
  35. Australian Research Council Future Fellowship [FT130101709]
  36. Medical Research Council programme [MC_UU_12013/4]
  37. The Netherlands Organisation for Health Research and Development (ZonMw), The Hague [6130.0031]
  38. NZO (Dutch Dairy Association), Zoetermeer
  39. Orthica, Almere
  40. Netherlands Consortium Healthy Ageing (NCHA) Leiden/Rotterdam
  41. Ministry of Economic Affairs, Agriculture and Innovation, The Hague [KB-15-004-003]
  42. Wageningen University, Wageningen
  43. VUmc, Amsterdam
  44. Erasmus Medical Center, Rotterdam
  45. National Heart Lung and Blood Institute (NHLBI) [HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, R01HL130114]
  46. National Institute of Neurological Disorders and Stroke (NINDS)
  47. National Center for Advancing Translational Sciences, CTSI [UL1TR000124]
  48. National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) [DK063491]
  49. Medical Research Council [G9321536, G9800062]
  50. MAFF [AN0523]
  51. EU FP5 [QLK6-CT-2002-02629]
  52. Food Standards Agency [N05046]
  53. GEFOS EU FP7 Integrated Project [201865]
  54. The UK's National Institute for Health Research (NIHR) Biomedical Research Centre Grant
  55. Estonian Genome Center University of Tartu (EGCUT)
  56. EU H2020 [692145, 676550, 654248]
  57. Estonian Research Council [IUT20-60]
  58. NIASC and EIT-Health through the European Regional Development Fund [2014-2020.4.01.15-0012]
  59. Netherlands Organisation for Scientific Research (NWO)
  60. Erasmus University Medical Centre
  61. the Centre for Medical Systems Biology (CMSB1 and CMSB2) of the Netherlands Genomics Initiative (NGI)
  62. National Institute for Arthritis
  63. Musculoskeletal and Skin Diseases and National Institute on Ageing [R01 AR41398, R01 AR 050066]
  64. National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195, N02-HL-6-4278]
  65. Swedish Research Council [K2010-54X-09894-19-3, 2006-3832, K2010-52X-20229-05-3]
  66. Swedish Foundation for Strategic Research
  67. ALF/LUA research grant in Gothenburg
  68. Lundberg Foundation
  69. Torsten and Ragnar Soderberg's Foundation
  70. Vastra Gotaland Foundation
  71. Goteborg Medical Society
  72. Novo Nordisk Foundation
  73. Intramural Research Program of the National Institute of Health (NIH)
  74. National Institute on Ageing
  75. US National Institute of Ageing (NIA) [N01AG62101, N01AG62103, N01AG62106, 1R01AG032098]
  76. Center for Inherited Disease Research (CIDR)
  77. National Institutes of Health [HHSN268200782096C]
  78. Hong Kong Research Grant Council (HKU) [768610M]
  79. Bone Health Fund of HKU Foundation
  80. KC Wong Education Foundation
  81. Committee on research and conference (CRCG) Grant
  82. Osteoporosis and Endocrine Research Fund
  83. Genomics Strategic Research Theme of the University of Hong Kong
  84. National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
  85. National Institute on Ageing (NIA)
  86. National Center for Research Resources (NCRR)
  87. National Institute of Health (NIH) [U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, UL1 RR024140]
  88. European Union's Seventh Framework Programme (FP7/2007-2013) [HEALTH-F2-2009-223004 PHASE]
  89. Netherlands Organisation of Scientific Research (NWO) Investments [175.010.2005.011, 911-03-012]
  90. Research Institute for Diseases in the Elderly [014-93-015]
  91. Netherlands Genomics Initiative/Netherlands Consortium for Healthy Ageing [050-060-810]
  92. German Bundesministerium fuer Forschung und Technology [01 AK 803 A-H, 01 IG 07015 G]
  93. Netherlands Organisation for Health Research and Development ZonMw VIDI [016.136.367]
  94. National Institute on Ageing (NIA) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) [R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, R01 AG026720]
  95. NIHR Biomedical Research Centre
  96. Chronic Disease Research Foundation
  97. Wellcome Trust
  98. Canadian Institutes of Health Research
  99. Canadian Foundation for Innovation
  100. Fonds de la Recherche en Sante Quebec
  101. Lady Davis Institute
  102. Jewish General Hospital
  103. Ministere du Developpement economique, de l'Innovation et de l'Exportation du Quebec
  104. University of Queensland [2014002959]
  105. University of Western Australia-University of Queensland Bilateral Research Collaboration Award [2014001711]
  106. National Health and Medical Research Council Early Career Fellowship [APP1104818]
  107. National Heart, Lung, and Blood Institute [HL 043851, HL69757]
  108. National Cancer Institute [CA 047988]
  109. Donald W Reynolds Foundation
  110. Fondation Leducq Amgen
  111. National Heart, Lung, and Blood Institute
  112. National Institutes of Health
  113. US. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]
  114. Academy of Finland [286284, 134309, 126925, 121584, 124282, 129378, 117787, 41071]
  115. Social Insurance Institution of Finland
  116. Tampere University Hospital [X51001]
  117. Turku University Hospital [X51001]
  118. Kuopio University Hospital [X51001]
  119. Juho Vainio Foundation
  120. Paavo Nurmi Foundation
  121. Finnish Foundation for Cardiovascular Research
  122. Finnish Cultural Foundation
  123. Tampere Tuberculosis Foundation
  124. Emil Aaltonen Foundation
  125. Yrjo Jahnsson Foundation
  126. Signe and Ane Gyllenberg Foundation
  127. Diabetes Research Foundation of Finnish Diabetes Association
  128. EU Horizon 2020 [755320]
  129. Red de Envejecimiento y fragilidad RETICEF
  130. CIBERER
  131. Instituto Carlos III. Fondos FEDER
  132. Fondo de Investigacion Sanitaria [FIS PI13/00116]
  133. Spanish MINECO [SAF2014-56562-R]
  134. Catalan Government [2014SGR932]
  135. BioPersMed [825329]
  136. Competence Center CBmed [844609]
  137. Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT)
  138. Austrian Federal Ministry of Economics and Labour/ the Federal Ministry of Economy, Family and Youth (BMWA/BMWFJ)
  139. Styrian Business Promotion Agency (SFG
  140. Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias [PI 06/34, PI09/539, PI12/615, PI15/521]
  141. Healthway Health Promotion Foundation of Western Australia
  142. Australasian Menopause Society
  143. Australian National Health and Medical Research Council [254627, 303169, 572604]
  144. Canadian Institutes for Health Research (CIHR) [MOP111103]
  145. Fonds du Recherche Quebec Sante
  146. Arthritis Research UK [15389]
  147. EU Biomed 1 [BMHICT920182, CIPDCT925012, ERBC1PDCT 940229, ERBC1PDCT930105]
  148. Wellcome Trust Collaborative Research Initiative 1995
  149. UK's National Institute for Health Research (NIHR) Biomedical Research Centre
  150. Canadian Institutes for health research [86748]
  151. University of Athens, Greece
  152. National Institute for Health Research (NIHR) Musculoskeletal BRU Oxford
  153. National Institute for Health Research (NIHR) Nutrition BRC Southampton
  154. The Hong Kong Jockey Club Charities Trust
  155. VC discretionary fund of The Chinese University of Hong Kong
  156. Research Grants Council [CUHK4101/02M.]
  157. Korea Health Technology R D Project
  158. Ministry of Health and Welfare, Republic of Korea [HI14C2258]
  159. Republic of Korea [HI15C0377]
  160. Netherlands Ministry of Health Welfare and Sports, Directorate of Long term Care
  161. Merck-Sharp-Dohme Chibret company
  162. European Union Strategic Educational Pathways Scholarhip scheme (STEPS)
  163. The Swedish Research Council [2006-3832, K201054X- 09894-19-3]
  164. World Anti-Doping Agency
  165. Danish Ministry of Culture
  166. Institute of Clinical Research of the University of Southern Denmark
  167. Slovenian research agency
  168. Ragnar Soderberg Foundation [E9/11]
  169. National Institute on Ageing/NIH [P01-AG005842, P01-AG005842-20S2, P30-AG012810, T32-AG000186-23]
  170. Swedish Department of Higher Education
  171. European Commission European Network for Genetic and Genomic Epidemiology (ENGAGE: 7th Framework Program [HEALTH-F4-2007-201413]
  172. GenomEUtwin: 5th Framework program Quality of Life and Management of the Living Resources [QLG2-CT-2002-01254]
  173. Swedish Foundation for Strategic Research [ICA08-0047]
  174. Jan Wallander and Tom Hedelius Foundation
  175. Swedish Council for Working Life and Social Research
  176. Swedish Sports Research Council [87/06]
  177. Swedish Society of Medicine
  178. Kempe-Foundation [JCK-1021]
  179. Medical Faculty of Umea University [ALFVLL: 968: 22-2005, ALFVL:-937-2006, ALFVLL: 223: 11-2007, ALFVLL: 78151-2009]
  180. county council of Vasterbotten [SpjutspetsanslagVLL: 159: 33-2007]
  181. Wellcome Trust [101123, 110141, 094134]
  182. National Institute on Arthritis Musculoskeletal and Skin Diseases [R01 AR041398]
  183. [R01AG023629]
  184. [201007176237]
  185. Medical Research Council [G9800062] Funding Source: researchfish
  186. MRC [MR/M004422/1, G9800062, MC_UU_12013/4, MC_U147585819, MR/N003284/1] Funding Source: UKRI

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OBJECTIVE To identify the genetic determinants of fracture risk and assess the role of 15 clinical risk factors on osteoporotic fracture risk. DESIGN Meta-analysis of genome wide association studies (GWAS) and a two-sample mendelian randomisation approach. SETTING 25 cohorts from Europe, United States, east Asia, and Australia with genome wide genotyping and fracture data. PARTICIPANTS A discovery set of 37 857 fracture cases and 227 116 controls; with replication in up to 147 200 fracture cases and 150 085 controls. Fracture cases were defined as individuals (> 18 years old) who had fractures at any skeletal site confirmed by medical, radiological, or questionnaire reports. Instrumental variable analyses were performed to estimate effects of 15 selected clinical risk factors for fracture in a twosample mendelian randomisation framework, using the largest previously published GWAS meta-analysis of each risk factor. RESULTS Of 15 fracture associated loci identified, all were also associated with bone mineral density and mapped to genes clustering in pathways known to be critical to bone biology (eg, SOST, WNT16, and ESR1) or novel pathways (FAM210A, GRB10, and ETS2). Mendelian bone mineral density on fracture risk. One standard deviation decrease in genetically determined bone mineral density of the femoral neck was associated with a 55% increase in fracture risk (odds ratio 1.55 (95% confidence interval 1.48 to 1.63; P= 1.5x10-68). Hand grip strength was inversely associated with fracture risk, but this result was not significant after multiple testing correction. The remaining clinical risk factors (including vitamin D levels) showed no evidence for an effect on fracture. CONCLUSIONS This large scale GWAS meta-analysis for fracture identified 15 genetic determinants of fracture, all of which also influenced bone mineral density. Among the clinical risk factors for fracture assessed, only bone mineral density showed a major causal effect on fracture. Genetic predisposition to lower levels of vitamin D and estimated calcium intake from dairy sources were not associated with fracture risk.

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