Assessment of the genetic and clinical determinants of fracture risk: genome wide association and mendelian randomisation study
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 randomisation analyses showed a clear effect of 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=1.5×10?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. Con clusions 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. ; Funding: This research and the Genetic Factors for Osteoporosis (GEFOS) consortium have been funded by the European Commission (HEALTH-F2-2008-201865-GEFOS). AGES: NIH contract N01- AG-12100 and NIA Intramural Research Program, Hjartavernd (the Icelandic Heart Association), and Althingi (the Icelandic Parliament). Icelandic Heart Association. Anglo-Australasian Osteoporosis Genetics Consortium (AOGC): National Health and Medical Research Council (Australia) (grant reference 511132). Australian Cancer Research Foundation and Rebecca Cooper Foundation (Australia). National Health and Medical Research Council (Australia). National Health and Medical Research Council (Australia) Career Development Award (569807). Medical Research Council New Investigator Award (MRC G0800582). Health Research Council of New Zealand. Sanofi-Aventis, Eli Lilly, Novartis, Pfizer, Proctor & Gamble Pharmaceuticals and Roche. National Health and Medical Research Council, Australia. 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. Medical Research Council UK and Arthritis Research UK. The Victorian Health Promotion Foundation and the Geelong Region Medical Research Foundation, and the National Health and Medical Research Council, Australia (project grant 628582). Action Research UK. DME is supported by an Australian Research Council Future Fellowship (FT130101709). This work was supported by a Medical Research Council programme grant (MC_UU_12013/4). B-Vitamins for the PRevention Of Osteoporotic Fractures (BPROOF) study: supported and funded so far by The Netherlands Organisation for Health Research and Development (ZonMw, grant 6130.0031), The Hague; unrestricted grant from NZO (Dutch Dairy Association), Zoetermeer; Orthica, Almere; Netherlands Consortium Healthy Ageing (NCHA) Leiden/Rotterdam; Ministry of Economic Affairs, Agriculture and Innovation (project KB-15-004-003), The Hague; Wageningen University, Wageningen; VUmc, Amsterdam; Erasmus Medical Center, Rotterdam. Cardiovascular Health Study (CHS): National Heart Lung and Blood Institute (NHLBI) contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and NHLBI grants U01HL080295, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the National Institute on Ageing (NIA). Genotyping supported in part by the National Center for Advancing Translational Sciences, CTSI grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. deCODE Genetics. EPIC-Norfolk: Medical Research Council G9321536 and G9800062, MAFF AN0523, EU FP5 (QLK6-CT-2002-02629), Food Standards Agency N05046, GEFOS EU FP7 Integrated Project Grant Reference: 201865, The UK's National Institute for Health Research (NIHR) Biomedical Research Centre Grant to Cambridge contributed to the costs of genotyping. Estonian Genome Center University of Tartu (EGCUT): This study was supported by EU H2020 grants 692145, 676550, 654248, Estonian Research Council Grant IUT20-60, NIASC and EIT—Health and EU through the European Regional Development Fund (project No 2014-2020.4.01.15-0012 GENTRANSMED). Erasmus Rucphen Family Study (ERF): Netherlands Organisation for Scientific Research (NWO), Erasmus University Medical Centre, the Centre for Medical Systems Biology (CMSB1 and CMSB2) of the Netherlands Genomics Initiative (NGI). Framingham Osteoporosis Study (FOS): National Institute for Arthritis, Musculoskeletal and Skin Diseases and National Institute on Ageing (R01 AR41398; DPK and R01 AR 050066; DK National Heart, Lung, and Blood Institute's Framingham Heart Study (N01-HC-25195) and its contract with Affymetrix for genotyping services (N02-HL-6-4278). The Gothenburg Osteoporosis and Obesity Determinan Study (GOOD): Swedish Research Council (K2010-54X-09894-19-3, 2006-3832 and K2010-52X-20229-05-3), Swedish Foundation for Strategic Research, ALF/LUA research grant in Gothenburg, Lundberg Foundation, Torsten and Ragnar Söderberg's Foundation, Västra Götaland Foundation, Göteborg Medical Society, Novo Nordisk Foundation, and European Commission grant HEALTH-F2-2008- 201865-GEFOS. Health Aging and Body Composition Study (HealthABC): the Intramural Research Program of the National Institute of Health (NIH), National Institute on Ageing. US National Institute of Ageing (NIA) contracts N01AG62101, N01AG62103, and N01AG62106. NIA grant 1R01AG032098. The Center for Inherited Disease Research (CIDR). National Institutes of Health contract number HHSN268200782096C. Hong Kong Osteoporosis Study (HKOS): Hong Kong Research Grant Council (HKU 768610M); Bone Health Fund of HKU Foundation; KC Wong Education Foundation; Small Project Funding (201007176237); Matching Grant, Committee on research and conference (CRCG) Grant and Osteoporosis and Endocrine Research Fund; and the Genomics Strategic Research Theme of the University of Hong Kong. The Osteoporotic Fractures in Men (MrOS) Study is supported by National Institutes of Health funding. The following institutes provide support: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institute on Ageing (NIA), National Center for Research Resources (NCRR), and National Institute of Health (NIH) Roadmap for Medical Research under the following grant numbers: U01 AR45580, U01 AR45614, U01 AR45632, U01 AR45647, U01 AR45654, U01 AR45583, U01 AG18197, U01-AG027810, and UL1 RR024140. Prospective study of pravastatin in the elderly at risk (PROSPER): European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement No HEALTH-F2-2009-223004 PHASE. Rotterdam study I, Rotterdam study II, Rotterdam study III: Netherlands Organisation of Scientific Research (NWO) Investments (No 175.010.2005.011, 911-03-012); Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Netherlands Genomics Initiative/Netherlands Consortium for Healthy Ageing (050-060-810); German Bundesministerium fuer Forschung und Technology under grants #01 AK 803 A-H and # 01 IG 07015 G. the Netherlands Organisation for Health Research and Development ZonMw VIDI 016.136.367 (funding FR, CM-G, KT). Study of Osteoporotic Fractures (SOF): supported by National Institutes of Health funding. The National Institute on Ageing (NIA) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, R01 AG027576, and R01 AG026720. TwinsUK1, TwinsUK2: NIHR Biomedical Research Centre (grant to Guys' and St Thomas' Hospitals and King's College London); Chronic Disease Research Foundation; Wellcome Trust; Canadian Institutes of Health Research, Canadian Foundation for Innovation, Fonds de la Recherche en Santé Québec, Lady Davis Institute, Jewish General Hospital, and Ministère du Développement économique, de l'Innovation et de l'Exportation du Quebec. UK Biobank: This research has been conducted using the UK Biobank Resource (application No 12703). Access to the UK Biobank study data was funded by a University of Queensland Early Career Researcher Grant (2014002959). Access to the UK Biobank study data was funded by University of Queensland Early Career Researcher Grant (2014002959) and University of Western Australia-University of Queensland Bilateral Research Collaboration Award (2014001711). NMW is supported by a National Health and Medical Research Council Early Career Fellowship (APP1104818). Women's Genome Health Study (WGHS): HL 043851 and HL69757 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W Reynolds Foundation, and the Fondation Leducq Amgen. Women's Health Initiative (WHI) program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. Young Finns study (YFS): has been financially supported by the Academy of Finland: grants 286284 (TL), 134309 (Eye), 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi); the Social Insurance Institution of Finland; Competitive State Research Financing of the Expert Responsibility area of Tampere, Turku and Kuopio University Hospitals (grant X51001); Juho Vainio Foundation; Paavo Nurmi Foundation; Finnish Foundation for Cardiovascular Research; Finnish Cultural Foundation; Tampere Tuberculosis Foundation; Emil Aaltonen Foundation; Yrjö Jahnsson Foundation; Signe and Ane Gyllenberg Foundation; and Diabetes Research Foundation of Finnish Diabetes Association; and EU Horizon 2020 (grant 755320 for TAXINOMISIS). Barcelona cohort osteoporosis (BARCOS): Red de Envejecimiento y fragilidad RETICEF, CIBERER, Instituto Carlos III. Fondos FEDER. Fondo de Investigación Sanitaria (FIS PI13/00116). Spanish MINECO (SAF2014-56562-R), Catalan Government (2014SGR932). Austrios-A, Austrios-B: was supported by BioPersMed (COMET K project 825329), and the Competence Center CBmed (COMET K1 centre 844609), funded by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT) and the Austrian Federal Ministry of Economics and Labour/ the Federal Ministry of Economy, Family and Youth (BMWA/BMWFJ) and the Styrian Business Promotion Agency (SFG). Cantabria-Camargo study (Cabrio-C), Cantabria osteoporosis case-control study (Cabrio-CC): Instituto de Salud Carlos III-Fondo de Investigaciones Sanitarias Grants PI 06/34,PI09/539, PI12/615 and PI15/521 (that could be cofunded by European Union-FEDER funds). Calcium Intake Fracture Outcome Study (CAIFOS): Healthway Health Promotion Foundation of Western Australia, Australasian Menopause Society and the Australian National Health and Medical Research Council Project Grant (254627, 303169 and 572604). Canadian Multicentre Osteoporosis Study (CaMos): was supported by a grant from the Canadian Institutes for Health Research (CIHR) (grant No MOP111103). JBR and JAM are funded by the Canadian Institutes of Health Research, Fonds du Recherche Québec Santé, and Jewish General Hospital. Edinburgh Osteoporosis Study (EDOS): was supported by a grant from Arthritis Research UK (grant number 15389). European Prospective Osteoporosis Study (EPOS): EU Biomed 1 (BMHICT920182, CIPDCT925012, ERBC1PDCT 940229, ERBC1PDCT930105), Medical Research Council G9321536 and G9800062, Wellcome Trust Collaborative Research Initiative 1995, MAFF AN0523,EU FP5 (QLK6-CT-2002-02629), Food Standards Agency N05046, GEFOS EU FP7 Integrated Project Grant Reference: 201865. The UK's National Institute for Health Research (NIHR) Biomedical Research Centre Grant to Cambridge contributed to the costs of genotyping. Geelong Osteoporosis Study (GEOS): Canadian Institutes for health research operating grant funding reference #86748. Genetic analysis of osteoporosis in Greece (GROS): University of Athens, Greece (Kapodistrias 2009). Hertfordshire Cohort Study (HCS): supported by Medical Research Council UK; Arthritis Research UK; National Institute for Health Research (NIHR) Musculoskeletal BRU Oxford; National Institute for Health Research (NIHR) Nutrition BRC Southampton. Hong Kong: The projects have been supported by The Hong Kong Jockey Club Charities Trust, VC discretionary fund of The Chinese University of Hong Kong, and Research Grants Council Earmarked Grant CUHK4101/02M. Korean osteoporosis study in Asan Medical Center (KorAMC): a grant of the Korea Health Technology R&D Project, the Ministry of Health and Welfare, Republic of Korea (project No HI14C2258); a grant of the Korea Health Technology R&D Project, the Ministry of Health and Welfare, Republic of Korea (project No HI15C0377). Longitudinal Aging Study Amsterdam (LASA): largely supported by a grant from the Netherlands Ministry of Health Welfare and Sports, Directorate of Long term Care. MINOS study was supported by a grant from the Merck-Sharp-Dohme Chibret company. Malta osteoporotic fracture study (MOFS): financial support was received from the European Union Strategic Educational Pathways Scholarhip scheme (STEPS). The Osteoporotic Fractures in Men (MrOS) Sweden: financial support was received from the Swedish Research Council (K2010- 54X-09894-19-3, 2006-3832), Swedish Foundation for Strategic Research, ALF/LUA research grant in Gothenburg, Lundberg Foundation, Torsten and Ragnar Söderberg's Foundation, Västra Götaland Foundation, Göteborg Medical Society, Novo Nordisk foundation, and European Commission grant HEALTH-F2-2008- 201865-GEFOS. Odense androgen study (OAS): World Anti-Doping Agency, Danish Ministry of Culture, Institute of Clinical Research of the University of Southern Denmark. Prevalence of osteoporosis in Slovenia (Slo-preval): was created as part of projects financially supported by the Slovenian research agency: P3-298 Geni, Hormoni in osebnostne spremembe pri hormonskih motnjah; Z1-3238: Genski in okoljski dejavniki tveganja za razvoj motnje pri remodellaciji kosti; J2-3314 Genetski faktorji in hormoni pri presnovnih boleznih; and J3-2330 Genetski dejavniki pri osteoporozi. TWINGENE: supported in part by the Ragnar Söderberg Foundation (E9/11); the National Science Foundation (EArly Concept Grants for Exploratory Research: "Workshop for the Formation of a Social Science Genetic Association Consortium," SES-1064089) as supplemented by the National Institutes of Health's (NIH) Office of Behavioural and Social Sciences Research; and the National Institute on Ageing/NIH through Grants P01-AG005842, P01-AG005842-20S2, P30-AG012810, and T32-AG000186-23 to the National Bureau of Economic Research. The Swedish Twin Registry is supported by the Swedish Department of Higher Education, European Commission European Network for Genetic and Genomic Epidemiology (ENGAGE: 7th Framework Program (FP7/2007-2013)/Grant agreement HEALTH-F4-2007-201413; and GenomEUtwin: 5th Framework program "Quality of Life and Management of the Living Resources" Grant QLG2-CT-2002-01254); NIH (DK U01-066134); Swedish Research Council (M-2005-1112 and 2009-2298); Swedish Foundation for Strategic Research (ICA08-0047); Jan Wallander and Tom Hedelius Foundation; and Swedish Council for Working Life and Social Research. The Umeå Fracture and Osteoporosis Study (UFO) is supported by the Swedish Research Council (K20006- 72X-20155013), Swedish Sports Research Council (87/06), Swedish Society of Medicine, Kempe-Foundation (JCK-1021), and by grants from the Medical Faculty of Umeå University (ALFVLL:968:22-2005, ALFVL:-937-2006, ALFVLL:223:11-2007, ALFVLL:78151-2009) and county council of Västerbotten (SpjutspetsanslagVLL:159:33-2007). GRW and JHDB were funded by the Wellcome Trust (Strategic Award grant No 101123; Joint Investigator Award No 110141; project grant No 094134). DPK was funded by a grant from the National Institute on Arthritis Musculoskeletal and Skin Diseases R01 AR041398. The funding agencies had no role in the study design, analysis, or interpretation of data; the writing of the manuscript; or in the decision to submit the article for publication.